Heterocyclic compounds, their production and use

ABSTRACT

A compound represented by the formula:  
                 
 
     wherein m is 1 or 2, R 1  is a halogen or an optionally halogenated C 1-2  alkyl; one of R 2  and R 3  is a hydrogen atom and the other is a group represented by the formula:  
                 
 
     wherein n is 3 or 4; R 4  is a C 1-4  alkyl group substituted by 1 or 2 hydroxy groups, or a salt thereof shows tyrosine kinase-inhibiting activity.

TECHNICAL FIELD

[0001] The present invention relates to a heterocyclic compound which isuseful as a growth factor receptor tyrosine kinase (particularly HER2)inhibitor, a method for its production, and a pharmaceutical compositioncontaining it.

BACKGROUND

[0002] Growth factor and growth factor receptor genes, known asproto-oncogenes, have play important roles in the pathology of humantumors such as breast cancer (Aronson et al., Science, Vol. 254, pp.1146-1153, 1991). Having homology to epidermal growth factor (EGF)receptor, the HER2 (human EGF receptor-2) gene encodestransmembrane-type glycoprotein, and this receptor possesses tyrosinekinase activity (Akiyama et al., Science, Vol. 232, pp. 1644-1646,1986). HER2 is found in human breast cancer and ovarian cancer (Slamonet al., Science, Vol. 244, pp. 707-712, 1989) and is also found inprostate cancer (Lyne et al., Proceedings of the American Associationfor Cancer Research, Vol. 37, p. 243, 1996) and gastric cancer (Yonemuraet al., Cancer Research, Vol. 51, p. 1034, 1991). In addition, thesubstrate for HER2 tyrosine kinase is found in 90% of cases ofpancreatic cancer. Transgenic mice incorporating the HER2 gene developbreast cancer as they grow (Guyre et al., Proceedings of the NationalAcademy of Science, USA, Vol. 89, pp. 10578-10582, 1992).

[0003] An antibody against HER2 was shown to suppress in vitroproliferation of cancer cells (McKenzie et al., Oncogene, Vol. 4, pp.543-548, 1989); in addition, a human monoclonal antibody against HER2provided encouraging results in a clinical study in breast cancerpatients (Baselga et al., Journal of Clinical Oncology, Vol. 14, pp.737-744, 1996).

[0004] These antibodies interfere with growth factors to bind to HER2and inhibit the activation of tyrosine kinase. Because these antibodieswere thus shown to suppress the progression of cancer in breast cancerpatients, drugs which directly inhibit HER2 tyrosine kinase were shownto be potentially effective as therapeutic drugs for breast cancer(Hayes, Journal of Clinical Oncology, Vol. 14, pp. 697-699, 1996).

[0005] As a compound that inhibits receptor type tyrosine kinases,including HER2, Japanese Patent Unexamined Publication No. 60571/1999discloses a compound represented by the formula:

[0006] wherein R is a is an aromatic heterocyclic group which may besubstituted; X is an oxygen atom, an optionally oxidized sulfur atom,—C(═O)— or —CH(OH)—; Y is CH or N; m is an integer from 0 to 10; n is aninteger from 1 to 5; the cyclic group:

[0007] is an aromatic azole group which may be substituted; Ring A maybe further substituted.

[0008] And, there is demand for the development of a compound whichpossesses excellent tyrosine kinase-inhibiting activity, which is of lowtoxicity, and which is satisfactory as a pharmaceutical.

DISCLOSURE OF INVENTION

[0009] The present inventors conducted various investigations onheterocyclic compounds possessing tyrosine kinase-inhibiting activityand succeeded in synthesizing for the first time a compound representedby the formula:

[0010] wherein m is 1 or 2;

[0011] R¹ is a halogen atom or an optionally halogenated C₁₋₂ alkylgroup;

[0012] one of R² and R³ is a a hydrogen atom and the other is a grouprepresented by the formula:

[0013] wherein n is 3 or 4; R⁴ is a C₁₋₄ alkyl group substituted by 1 to2 hydroxy groups (hereinafter also referred to as Compound (I)), whichhas a chemical structure unique in that phenyl of the phenylethenyl ofthe skeleton represented by the formula:

[0014] wherein the symbols have the same definitions as those shownbelow is substituted by a halogen or an optionally halogenated C₁₋₂alkyl, or a salt thereof, and found that this Compound (I) or a saltthereof possesses an unexpectedly excellent tyrosine kinase-inhibitingactivity based on its unique chemical structure. The inventors conductedfurther investigations based on this finding and developed the presentinvention.

[0015] Accordingly, the present invention relates to:

[0016] (1) A compound (I) or a salt thereof;

[0017] (2) A compound as defined in (1) above, wherein R¹ is fluoro ortrifluoromethyl, or a salt thereof;

[0018] (3) A compound as defined in (1) above, wherein R² is a grouprepresented by the formula:

[0019] and R³ is a hydrogen atom; or

[0020] R² is a hydrogen atom and R³ is a group represented by theformula:

[0021] or a salt thereof;

[0022] (4) A compound as defined in (1) above, wherein R² is a grouprepresented by the formula:

[0023] and R³is a hydrogen atom, or a salt thereof;

[0024] (5) A compound as defined in (1) above, wherein m is 1;

[0025] R¹ is 4-trifluoromethyl;

[0026] R² is a group represented by the formula:

[0027] and R³ is a hydrogen atom, or a salt thereof;

[0028] (6) A compound as defined in (1) above, which is1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole,1-(3-{3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole,or

[0029]3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol,or a salt thereof;

[0030] (7) A method for producing Compound (I) or a salt thereofcomprising reacting a compound represented by the formula:

[0031] wherein, X is a leaving group; the other symbols have the samemeanings as defied above, or a salt thereof, with a compound representedby the formula:

[0032] wherein the symbols have the same meanings as defied above, or asalt thereof;

[0033] (8) A pro-drug of a compound as defined in (1) above;

[0034] (9) A pharmaceutical composition containing a compound as definedin (1) above or a salt thereof or a pro-drug thereof;

[0035] (10) A pharmaceutical composition as defined in (9) above, whichis a tyrosine kinase inhibitor;

[0036] (11) A pharmaceutical composition as defined in (9) above, whichis an agent for preventing or treating cancer;

[0037] (12) A pharmaceutical composition as defined in (11) above,wherein the cancer is breast cancer or prostate cancer;

[0038] (13) A pharmaceutical composition as defined in (11) above,wherein the cancer is lung cancer;

[0039] (14) A pharmaceutical composition which combines a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and otheranti-cancer agents;

[0040] (15) A pharmaceutical composition which combines a compound asdefined in (1) above or a salt thereof or a pro-drug thereof andhormonal therapeutic agents;

[0041] (16) The pharmaceutical composition as defined in (15) above,wherein the hormonal therapeutic agent is a LH-RH modulator;

[0042] (17) The pharmaceutical composition as defined in (16) above,wherein the LH-RH modulator is LH-RH antagonist;

[0043] (18) The pharmaceutical composition as defined in (17) above,wherein the LH-RH antagonist is leuprorelin or a salt thereof;

[0044] (19) A method for inhibiting tyrosine-kinase which comprisesadministering an effective amount of a compound as defined in (1) aboveor a salt thereof or a pro-drug thereof to mammals;

[0045] (20) A method for preventing or treating cancer which comprisesadministering an effective amount of a compound as defined in (1) aboveor a salt thereof or a pro-drug thereof to mammals;

[0046] (21) A method for preventing or treating cancer which comprisescombining [1] administering an effective amount of a compound as definedin (1) above or a salt thereof or a pro-drug thereof to mammals and [2]1 to 3 selected from the group consisting (i) administering an effectiveamount of other anti-cancer agents to mammals, (ii) administering aneffective amount of hormonal therapeutic agents to mammals and (iii)non-drug therapy;

[0047] (22) The method as defined in (21) above wherein non-drug therapyis surgery, hypertensive chemotherapy, genetherapy, thermotherapy,cryotherapy, laser cauterization and/or radiotherapy;

[0048] (23) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of other anti-cancer agents to mammals;

[0049] (24) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of hormonal therapeutic agents to mammals;

[0050] (25) The method as defined in (24) above, wherein the hormonaltherapeutic agent is a LH-RH modulator;

[0051] (26) The method as defined in (25) above, wherein the LH-RHmodulator is LH-RH antagonist;

[0052] (27) The method as defined in (26) above, wherein the LH-RHantagonist is leuprorelin or a salt thereof;

[0053] (28) A method for preventing or treating cancer which comprisesadministering an effective amount of a compound as defined in (1) aboveor a salt thereof or a pro-drug thereof to mammals before surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0054] (29) A method for preventing or treating cancer which comprisesadministering an effective amount of a compound as defined in (1) aboveor a salt thereof or a pro-drug thereof to mammals after surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0055] (30) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of other anti-cancer agents to mammals before surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0056] (31) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of other anti-cancer agents to mammals before surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0057] (32) The method as defined in (31) above, wherein the hormonaltherapeutic agent is a LH-RH modulator;

[0058] (33) The method as defined in (32) above, wherein the LH-RHmodulator is LH-RH antagonist;

[0059] (34) The method as defined in (33) above, wherein the LH-RHantagonist is leuprorelin or a salt thereof;

[0060] (35) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of other anti-cancer agents to mammals after surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0061] (36) A method for preventing or treating cancer which comprisesadministering in combination of an effective amount of a compound asdefined in (1) above or a salt thereof or a pro-drug thereof and aneffective amount of other anti-cancer agents to mammals after surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization and/or radiotherapy;

[0062] (37) The method as defined in (36) above, wherein the hormonaltherapeutic agent is a LH-RH modulator;

[0063] (38) The method as defined in (37) above, wherein the LH-RHmodulator is LH-RH antagonist;

[0064] (39) The method as defined in (38) above, wherein the LH-RHantagonist is leuprorelin or a salt thereof;

[0065] (40) Use of a compound as defined in (1) above or a salt thereofor a pro-drug thereof for preparing a tyrosine kinase inhibitor;

[0066] (41) Use of a compound as defined in (1) above or a salt thereofor a pro-drug thereof for preparing an agent for preventing or treatingcancer;

[0067] (42) A compound represented by the formula:

[0068] wherein R^(1a) is fluoro or trifluoromethyl, X¹ is a leavinggroup, and n is 3 or 4, or a salt thereof;

[0069] (43) A compound as defined in (42) above, wherein X¹ is a halogenatom; and

[0070] (44) Use of a compound as defined in (42) above or a salt thereoffor preparing a compound as defied in (1) above.

[0071] With respect to the formula above, the “halogen atom” representedby R¹ is exemplified by fluoro, chloro, bromo, and iodo. In particular,fluoro is preferred.

[0072] The “halogen” of the “optionally halogenated C₁₋₂ alkyl group”represented by R¹ is exemplified by fluoro, chloro, bromo, and iodo. Inparticular, fluoro is preferred.

[0073] The “C₁₋₂ alkyl group” of the “optionally halogenated C₁₋₂ alkylgroup” represented by R¹ is exemplified by methyl and ethyl, and methylis preferred.

[0074] Said “C₁₋₂ alkyl group” may have 1 to 3, preferably 2 or 3,halogens mentioned above at any possible positions; when 2 or more suchhalogens are present, they may be identical or different.

[0075] As specific examples of said “optionally halogenated C₁₋₂ alkylgroup”, there may be mentioned methyl, ethyl, and trifluoromethyl.

[0076] R¹ is preferably a halogen atom or a halogenated C₁₋₂ alkylgroup, and fluoro and trifluoromethyl are more preferable.

[0077] When m is 2, the R¹ groups may be different.

[0078] The group represented by R² or R³ for the formula:

[0079] wherein R⁴ has the same meanings as defined above, is preferablya group represented by the formula:

[0080] wherein R⁴ has the same meaning as defined above.

[0081] As examples of the “C₁₋₄ alkyl group” of the “C₁₋₄ alkyl groupsubstituted by 1 or 2 hydroxy groups” represented by R⁴, there may bementioned methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,and tert-butyl. In particular, ethyl, propyl, etc. are preferred.

[0082] As examples of said “C₁₋₄ alkyl group substituted by 1 to 2hydroxy groups,” there may be mentioned 2-hydroxyethyl,2,3-dihydroxypropyl, and 1,3-dihydroxypropyl. In particular,2,3-dihydroxypropyl is preferred.

[0083] n is preferably 3. With respect to the formula above, it ispreferable that R² is a group represented by the formula:

[0084] and R³ is a hydrogen atom.

[0085] It is also preferable that R² is a hydrogen atom and R³ is agroup represented by the formula:

[0086] It is also preferable that R² is a group represented by theformula:

[0087] wherein n has the same meaning as defined above, and R³ is ahydrogen atom, with n being more preferably 4.

[0088] As a preferable example of Compound (I), there may be mentioned acompound represented by the formula:

[0089] wherein the symbols have the same meaning as defined above, or asalt thereof.

[0090] Of Compound (I), a compound wherein m is 1; R¹ is4-trifluoromethyl; R² is a group represented by the formula:

[0091] and R³ is a hydrogen atom, or a salt thereof is preferred.

[0092] As specific examples of Compound (I), there may be mentioned1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl)-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole,1-(3-{3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl)-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole,3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol,or salts thereof.

[0093] As the salt of Compound (I) of the present invention,pharmaceutically acceptable salts are preferred, including salts withinorganic bases, salts with organic bases, salts with inorganic acids,salts with organic acids, and salts with basic or acidic amino acids. Aspreferable examples of salts with inorganic bases, there may bementioned alkali metal salts such as sodium salt and potassium salt;alkaline earth metal salts such as calcium salt and magnesium salt;aluminum salt; and ammonium salt. As preferable examples of salts withorganic bases, there may be mentioned salts with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc.As preferable examples of salts with inorganic acids, there may bementioned salts with hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, etc. As preferable examples of saltswith organic acids, there may be mentioned salts with formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.As preferable examples of salts with basic amino acids, there may bementioned salts with arginine, lysine, ornithine, etc.; as preferableexamples of salts with acidic amino acids, there may be mentioned saltswith aspartic acid, glutamic acid, etc.

[0094] In Compound (I), two kinds, i.e., (Z)-ethenyl configuration and(E)-ethenyl configuration, are present; these isomers are included inthe scope of the present invention, whether they are present in the formof simple substances or mixtures.

[0095] Furthermore, when Compound (I) has asymmetric carbons, opticalisomers exist; these isomers are included in the scope of the presentinvention, whether they are present in the form of simple substance ormixtures.

[0096] Compound (I) of the present invention or a salt thereof isobtained by commonly known methods, e.g., a method based on the methoddescribed in Japanese Patent Unexamined Publication No. 60571/1999, andis also obtained by, for example, the methods schematized by ReactionFormulas A through H below.

[0097] The symbols for the compounds given in the schemes for thereaction formulas below have the same definitions as those shown above.The compounds shown in the reaction formulas include salts thereof;examples of such salts include the same salts as those of Compound (I).

[0098] As examples of the “leaving group” represented by X, there may bementioned halogens (e.g., chloro, bromo) or a group represented by theformula: —OSO₂R⁵ wherein R⁵ is an alkyl or an aryl optionally having asubstituent.

[0099] As examples of the “alkyl” represented by R⁵, there may bementioned C₁₋₆ alkyl such as methyl, ethyl, and propyl.

[0100] As examples of the “aryl” of the “aryl optionally having asubstituent” represented by R⁵, there may be mentioned C₆₋₁₄ aryls suchas phenyl.

[0101] The “substituent” of the “aryl optionally having a substituent”represented by R⁵ is exemplified by C₁₋₆ alkyls such as methyl, ethyl,and propyl.

[0102] As specific examples of said “aryl optionally having asubstituent,” there may be mentioned phenyls (e.g., p-tolyl) which mayhave a C₁₋₆ alkyl.

[0103] Compound (II) and Compound (III) are reacted to yield Compound(I).

[0104] This condensation reaction is usually carried out in the presenceof a base between Compound (II) and Compound (III).

[0105] As examples of said “base,” there may be mentioned alkali metalor alkaline earth metal hydroxides (e.g., sodium hydroxide, potassiumhydroxide), alkali metal or alkaline earth metal carbonates (e.g.,sodium hydrogen carbonate, sodium carbonate, potassium carbonate),amines (e.g., pyridine, triethylamine, N,N-dimethylaniline), alkalimetal or alkaline earth metal hydrides (e.g., sodium hydride, potassiumhydride, calcium hydride), and alkali metal or alkaline earth metallower alkoxides (e.g., sodium methoxide, sodium ethoxide, potassiumtert-butoxide).

[0106] The amount of “base” used is preferably about 1 to 5 mol per molof Compound (II).

[0107] The amount of “Compound (III)” used is preferably about 0.5 to 5mol per mol of Compound (II).

[0108] This reaction is advantageously carried out in the presence of abase which does not interfere with the reaction. Said solvent is notsubject to limitation, as long as the reaction proceeds; as examples ofthis solvent, aromatic hydrocarbons, ethers, ketones, halogenatedhydrocarbons, amides, sulfoxides or mixtures of two or more kindsthereof may be used.

[0109] Reaction temperature is normally −50 to +150° C., preferablyabout −10 to +100° C. Reaction time is normally 0.5 to 48 hours.

[0110] Compound (II) can be produced by a commonly known method or amodification thereof, e.g., Compound (IIa), wherein X is chloro, can beproduced by the method shown by Reaction Formula B below, or the like.

[0111] Compound (IV) and 1,3-dichloroacetone are subjected to acondensation/dehydration reaction to yield Compound (IIa).

[0112] If available commercially, Compound (IV) may be used as acommercial product as is, or may be produced by a commonly known method,a modification thereof, or the like.

[0113] The amount of “1,3-dichloroacetone” used is about 1 equivalent toa large excess (amount of solvent) relative to Compound (IV).

[0114] This reaction is advantageously carried out in the absence ofsolvent or in the presence of solvent which does not interfere with thereaction. Said solvent is not subject to limitation, as long as thereaction proceeds; as examples of this solvent, aromatic hydrocarbons,ethers, ketones, halogenated hydrocarbons or mixtures of two or morekinds thereof may be used.

[0115] Reaction temperature is normally 50 to 150° C., preferably about60 to 120° C. Reaction time is normally 0.5 to 48 hours.

[0116] Although the product can be used for the next reaction in theform of a reaction mixture as-is, or in the form of a crude product, itcan also be isolated from the reaction mixture by a conventional method.

[0117] Of Compound (III), Compound (IIIa), wherein R³ is a hydrogenatom, can be produced by a commonly known method or a modificationthereof, e.g., the method shown by Reaction Formula C below.

[0118] With respect to the formula above, P^(a) is a hydrogen atom or aprotective group; X^(a) is a leaving group.

[0119] As examples of the “protective group” represented by P^(a), theremay be mentioned alkyls (e.g., C₁₋₆ alkyls such as methyl and ethyl),phenyl-C₁₋₆ alkyls (e.g., benzyl), C₁₋₆ alkylcarbonyl, alkyl-substitutedsilyl (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0120] As examples of the “leaving group” represented by X^(a), theremay be mentioned the same examples as those of the “leaving group”represented by X above.

[0121] By condensing Compound (V) and Compound (VI) or Compound (VII) toyield Compound (VIII), which is subjected to a deprotecting reaction asnecessary, Compound (IIIa) is obtained.

[0122] If available commercially, each of Compound (V), Compound (VI)and Compound (VII) may be used as a commercial product as is, or may beproduced by a commonly known method, a modification thereof, or thelike.

[0123] Said “condensation reaction” is normally carried out in thepresence of a base in a solvent which does not interfere with thereaction.

[0124] Said “base” is exemplified by the bases described in detail withrespect to Reaction Formula A above.

[0125] The amount of “base” used is preferably about 1 to 5 mol per molof Compound (V).

[0126] The amount of Compound (VI) or Compound (VII) used is preferablyabout 0.5 to 5 mol per mol of Compound (V).

[0127] Said solvent is not subject to limitation, as long as thereaction proceeds; as examples of this solvent, aromatic hydrocarbons,ethers, ketones, halogenated hydrocarbons, amides, sulfoxides ormixtures of two or more kinds thereof may be used.

[0128] The reaction temperature is normally −50 to +150° C., preferablyabout −10 to +100° C. Reaction time is about 0.5 to 48 hours.

[0129] Although Compound (VIII) obtained can be used for the nextreaction in the form of a reaction mixture as-is, or in the form of acrude product, it can also be isolated from the reaction mixture by aconventional method.

[0130] Said “deprotection reaction” can be carried out by anappropriately selected conventional method.

[0131] When P^(a) is an alkyl, for example, Compound (VIII) is subjectedto a treatment with an acid (e.g., mineral acid such as hydrobromicacid, or Lewis acid such as titanium tetrachloride).

[0132] When P^(a) is a phenyl-C₁₋₆ alkyl, for example, Compound (VIII)is subjected to a hydrogenation reaction.

[0133] When P^(a) is an alkyl-substituted silyl, for example, Compound(VIII) is reacted with a fluoride (e.g., tetrabutylammonium fluoride).

[0134] Although Compound (IIIa) obtained can be used for the nextreaction in the form of a reaction mixture as-is, or in the form of acrude product, it can also be isolated from the reaction mixture by aconventional method.

[0135] Of Compound (III), Compound (IIIb), wherein R² is a hydrogenatom, can be produced by a commonly known method or a modificationthereof, e.g., the method shown by Reaction Formula D below.

[0136] With respect to the formula above, P^(b) is a hydrogen atom or aprotective group; X^(b) is a leaving group.

[0137] The “protective group” represented by P^(b) is the same as the“protective group” represented by P^(a) above.

[0138] The “leaving group” represented by X^(b) is, for example, thesame as the leaving group represented by X above.

[0139] In the same manner as the method described with respect toReaction Formula C above, Compound (IX) and Compound (VI) or Compound(VII) are condensed to yield Compound (X), which is then subjected to adeprotection reaction as necessary to yield Compound (IIIb).

[0140] If available commercially, Compound (IX) may be used as acommercial product as is, or may be produced by a commonly known method,a modification thereof, or the like.

[0141] Of Compound (I), Compound (Ia), wherein R³ is a hydrogen atom,can also be produced by the method shown by Reaction Formula E below.

[0142] With respect to the formula above, X^(c) is a leaving group.

[0143] The “leaving group” represented by X^(c) is, for example, thesame as the leaving group represented by X above.

[0144] Compound (XI) and Compound (VI) or Compound (VII) are reacted toyield Compound (Ia).

[0145] This condensation reaction is normally carried out in thepresence of a base between Compound (XI) and Compound (VI) or Compound(VII).

[0146] Said “base” is exemplified by the base described in detail withrespect to Reaction Formula A above.

[0147] The amount of “base” used is preferably about 1 to 5 mol per molof Compound (XI).

[0148] The amount of each of Compound (VI) and Compound (VII) used ispreferably about 0.5 to 5 mol per mol of Compound (XI).

[0149] This reaction is advantageously carried out in the presence ofsolvent that does not interfere with the reaction. Said solvent is notsubject to limitation, as long as the reaction proceeds, and isexemplified by aromatic hydrocarbons, ethers, ketones, halogenatedhydrocarbons, amides, sulfoxides, or mixtures of two or more kindsthereof.

[0150] The reaction temperature is normally −20 to +150° C., preferablyabout −10 to +100° C. The reaction time is normally 0.5 to 48 hours.

[0151] Compound (XI) can be produced by a commonly known method or amodification thereof, e.g., the method shown by Reaction Formula Fbelow.

[0152] With respect to the formula above, X^(d) is a leaving group.

[0153] The “leaving group” represented by X^(d) is, for example, thesame as the leaving group represented by X above, and is preferably aleaving group which is less reactive than X.

[0154] In the same manner as the method described with respect toReaction Formula A above, Compound (II) and Compound (XII) are reactedto yield Compound (XI).

[0155] If available commercially, Compound (XII) may be used as acommercial product as is, or may be produced by a commonly known method,a modification thereof, or the like.

[0156] Of Compound (I), Compound (Ib), wherein R² is a hydrogen atom,can also be produced by the method shown by Reaction Formula G below.

[0157] With respect to the formula above, X^(e) is a leaving group.

[0158] The “leaving group” represented by X^(e) is, for example, thesame as the leaving group represented by X above.

[0159] In the same manner as the method described with respect toReaction Formula E above, Compound (XIII) and Compound (VI) or Compound(VII) are reacted to yield Compound (Ib).

[0160] Compound (XIII) can be produced by a commonly known method or amodification thereof, e.g., the method shown by Reaction Formula Hbelow.

[0161] With respect to the formula above, X^(f) is a leaving group.

[0162] The “leaving group” represented by X^(f) is, for example, thesame as the leaving group represented by X above, and is preferably aleaving group which is less reactive than X.

[0163] In the same manner as the method described with respect toReaction Formula A above, Compound (II) and Compound (XIV) are reactedto yield Compound (XIII).

[0164] If available commercially, Compound (XIV) may be used as acommercial product as is, or may be produced by a commonly known method,a modification thereof, or the like.

[0165] As the aforementioned “aromatic hydrocarbons,” for example,benzene, toluene, xylene, etc. are used.

[0166] As the aforementioned “ethers,” for example, tetrahydrofuran,dioxane, etc. are used.

[0167] As the aforementioned “ketones,” for example, acetone,2-butanone, etc. are used.

[0168] As the aforementioned “halogenated hydrocarbons,” for example,chloroform, dichloromethane, etc. are used.

[0169] As the aforementioned “amides,” for example,N,N-dimethylformamide etc. are used.

[0170] As the aforementioned “sulfoxides,” for example,dimethylsulfoxide etc. are used.

[0171] In each reaction mentioned above, if the product is obtained as afree form, it can be converted into a salt thereof by a conventionalmethod; if the product is obtained as a salt, it can be converted into afree form thereof by a conventional method.

[0172] In the reactions mentioned above, if amino (NH₂), hydroxy (OH),carboxyl (COOH), or the like is contained in a substituent, the startingmaterial may have these groups protected and the protective groups maybe removed by a commonly known method after the reaction to produce thedesired product. As amino-protecting groups, there may be,mentionedacyls (e.g., C₁₋₆ alkylcarbonyls such as acetyl; benzyloxycarbonyl; C₁₋₆alkoxy-carbonyls such as tert-butoxycarbonyl; phthaloyl; formyl). Asexamples of hydroxy-protecting groups, there may be mentioned C₁₋₆alkyls (e.g., methyl, ethyl), phenyl-C₁₋₆ alkyls (e.g., benzyl), C₁₋₆alkylcarbonyls (e.g., acetyl), benzoyl, and alkyl-substituted silyls(e.g., trimethylsilyl, tert-butyldimethylsilyl). As examples ofcarboxyl-protecting groups, there may be mentioned C₁₋₆ alkyls (e.g.,methyl, ethyl), and phenyl-C₁₋₆ alkyls (e.g., benzyl).

[0173] Compound (I) [Including (Ia) and (Ib)] thus obtained can beisolated and purified by commonly known means for separation, e.g.,concentration, concentration under reduced pressure, solvent extraction,crystallization, recrystallization, re-dissolution, and chromatography.

[0174] If Compound (I) is obtained as a free form, it can be convertedinto a desired salt by a commonly known method or a modificationthereof; conversely, if Compound (I) is obtained as a salt, it can beconverted into a free form or another desired salt by a commonly knownmethod or a modification thereof.

[0175] Compound (I) may be a hydrate or a non-hydrate.

[0176] When Compound (I) is obtained as a mixture of optical isomers,the desired (R)-configuration or (S)-configuration can be separated by acommonly known means of optical resolution.

[0177] Compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C) orthe like.

[0178] A compound represented by the formula:

[0179] wherein R^(1a) is fluoro or trifluoromethyl, X¹ is a leavinggroup, and n is 3 or 4, or a salt thereof is a new intermediate forproducing the compound (I) of the present invention or a salt thereof.

[0180] As examples of the “leaving group” represented by X¹, there maybe mentioned the same examples as those of the “leaving group”represented by X above, and of them, halogen (e.g., chloro, bromo) ispreferable.

[0181] As the salts of the compound (IIa), the same examples as those ofthe compound (I) can be used.

[0182] A pro-drug of the compound (I) or a salt thereof (hereinafterreferred to as the compound (I)) means a compound which is converted tothe compound (I) of the present invention under the physiologicalcondition or with a reaction due to an enzyme, an gastric acid, etc. inthe living body, that is, a compound which is converted to the compound(I) of the present invention with oxidation, reduction, hydrolysis, etc.according to an enzyme; a compound which is converted to the compound(I) of the present invention with gastric acid, etc.

[0183] Examples of the pro-drug of the compound (I) of the presentinvention include a compound wherein an hydroxy group of the compound(I) of the present invention is substituted with acyl, alkyl, phosphoricacid, boric acid, etc. (e.g. a compound wherein an hydroxy group of thecompound (I) of the present invention is substituted with acetyl,palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl, etc.) etc. These pro-drug can be producedby per se known method from the compound (I) of the present invention.

[0184] The pro-drug of the compound (I) of the present invention may bea compound which is converted into the compound (I) of the presentinvention under the physiological conditions as described in“Pharmaceutical Research and Development”, Vol. 7 (Drug Design), pages163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan).

[0185] The compound (I) of the present invention or a salt thereof or apro-drug thereof (hereinafter referred to as the compound of the presentinvention) possesses tyrosine kinase-inhibiting activity and can be usedto prevent or treat tyrosine kinase-dependent diseases in mammals.Tyrosine kinase-dependent diseases include diseases characterized byincreased cell proliferation due to abnormal tyrosine kinase activity.Furthermore, the compound of the present invention or a salt thereofspecifically inhibits HER2 tyrosine kinase and is therefore also usefulas a therapeutic agent for suppressing the growth of HER2-expressingcancer, or a preventive agent for preventing the transition ofhormone-dependent cancer to hormone-independent cancer.

[0186] Accordingly, the compound of the present invention can be used asa safe preventive or therapeutic agent for diseases due to abnormal cellproliferation such as various cancers (particularly breast cancer,prostate cancer, pancreatic cancer, gastric cancer, lung cancer, coloncancer, rectal cancer, esophagus cancer, duodenal cancer, cancer of thetongue, cancer of pharynx, cerebral cancer, neurilemoma, non-small celllung cancer, small cell lung cancer, liver cancer, kidney cancer, cancerof the bile duct, cancer of the uterine body, cancer of the uterinecervix, ovarian cancer, bladder cancer, skin cancer, hemangioma,malignant lymphoma, malignant melanoma, thyroid carcancer, bone tumors,vascular fibroma, retinoblastoma, penile cancer, tumor in childhood,Kaposi's sarcoma, Kaposi's sarcoma derived from AIDS, maxillary tumor,fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, leukemia, etc.),atheroma arteriosclerosis, angiogenesis (e.g., angiogenesis associatedwith growth of solid cancer and sarcoma, angiogenesis associated withtumor metastasis, and angiogenesis associated with diabeticnephropathy), and viral diseases (HIV infection etc.).

[0187] Tyrosine kinase-dependent diseases further include cardiovasculardiseases associated with abnormal tyrosine kinase activity. The compoundof the present invention can therefore be used as a preventive ortherapeutic agent for cardiovascular diseases such as like re-stenosis.

[0188] The compound of the present invention is useful as an anticanceragent for preventing or treating cancers, e.g., breast cancer, prostatecancer, pancreatic cancer, gastric cancer, lung cancer, colonic cancer,carcinoma of the colon and rectum. The compound of the present inventionis of low toxicity and can be used as a pharmaceutical compositionas-is, or in a mixture with a commonly known pharmaceutically acceptablecarrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats,rats, mice, rabbits, pigs, monkeys).

[0189] In addition to the compound of the present invention, saidpharmaceutical composition may contain other active ingredients, e.g.,the following hormone therapy agents, chemotherapy agents, immunotherapyagents, or drugs which inhibit the activity of cell growth factors andreceptors thereof.

[0190] As a pharmaceutical for mammals such as humans, the compound ofthe present invention can be administered orally in the form of, forexample, capsules (including soft capsules and microcapsules), powders,and granules, or non-orally in the form of injections, suppositories,and pellets.

[0191] Examples of the parenteral administration route includeintravenous, intramuscular, subcutaneous, intra-tissue, intranasal,intradermal, instillation, intracerebral, intrarectal, intravaginal,intraperitoneal, intratumoral, juxtaposion of tumor and administrationdirectly to the lesion.

[0192] The dose of the compound varies depending on the route ofadministration, symptoms, etc. For example, when it is administeredorally as an anticancer agent to a patient (body weight 40 to 80 kg)with breast cancer or prostate cancer, its dose is, for example, 0.5 to100 mg/kg body weight per day, preferably 1 to 50 mg/kg body weight perday, and more preferably 1 to 25 mg/kg body weight per day. This amountmay be administered once or in 2 to 3 divided portions daily.

[0193] Desired compound of the present invention can be formulated witha pharmaceutically acceptable carrier and administered orally ornon-orally in the form of solid preparations such as tablets, capsules,granules and powders; or liquid preparations such as syrups andinjectable preparations.

[0194] As pharmaceutically acceptable carriers, there may be usedvarious organic or inorganic carrier substances in common use forpharmaceutical preparations, including excipients, lubricants, binders,and disintegrating agents in solid preparations; solvents, dissolutionaids, suspending agents, isotonizing agents, buffers, and soothingagents in liquid preparations. Such pharmaceutical additives asantiseptics, antioxidants, coloring agents, and sweetening agents canalso be used as necessary.

[0195] As examples of preferable excipients, there may be mentioned, forexample, lactose, sucrose, D-mannitol, starch, crystalline cellulose,and light silicic anhydride.

[0196] As examples of preferable lubricants, there may be mentioned, forexample, magnesium stearate, calcium stearate, talc, and colloidalsilica.

[0197] As examples of preferable binders, there may be mentioned, forexample, crystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, andpolyvinylpyrrolidone.

[0198] As examples of preferable disintegrating agents, there may bementioned, for example, starch, carboxymethyl cellulose, carboxymethylcellulose calcium, crosslinked carmellose sodium, and carboxymethylstarch sodium.

[0199] As examples of preferable solvents, there may be mentioned, forexample, water for injection, alcohol, propylene glycol, macrogol,sesame oil, and corn oil.

[0200] As examples of preferable dissolution aids, there may bementioned, for example, polyethylene glycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol,triethanolamine, sodium carbonate, and sodium citrate.

[0201] As examples of preferable suspending agents, there may bementioned, for example, surfactants such as stearyltriethanolamine,sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkoniumchloride, benzetonium chloride, and monostearic glycerol; andhydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone,carboxymethyl cellulose sodium, methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

[0202] As examples of preferable isotonizing agents, there may bementioned, for example, sodium chloride, glycerol, and D-mannitol.

[0203] As examples of preferable buffers, there may be mentioned, forexample, buffer solutions of phosphates, acetates, carbonates, citrates,etc.

[0204] As examples of preferable soothing agents, there may bementioned, for example, benzyl alcohol.

[0205] As examples of preferable antiseptics, there may be mentioned,for example, para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0206] As examples of preferable antioxidants, there may be mentioned,for example, sulfites and ascorbic acid.

[0207] A pharmaceutical composition can be produced by a conventionalmethod by containing the compound of the present invention in a ratio ofnormally 0.1 to 95% (w/w) to the total amount of the preparation,although the ratio varies depending on dosage form, method ofadministration, carrier, etc.

[0208] And, a combination of (1) administering an effective amount of acompound as claimed in claim 1 or a salt thereof or a pro-drug thereofto mammals and (2) 1 to 3 selected from the group consisting (i)administering an effective amount of other anti-cancer agents tomammals, (ii) administering an effective amount of hormonal therapeuticagents to mammals and (iii) non-drug therapy can prevent and/or treatcancer effectively. As the non-drug therapy, for example, surgery,hypertensive chemotherapy, genetherapy, thermotherapy, cryotherapy,laser cauterization, radiotherapy, etc. are exemplified and more thantwo kinds of these may be combined. For example, the compound of thepresent invention can be administered to the same subject simultaneouslywith hormonal therapeutic agents, anticancer agent (e.g.,chemotherapeutic agents, immunotherapeutic agents, or drugs that inhibitthe activity of growth factors or growth factor receptors) (after here,these are referred to as a combination drug).

[0209] Although the compound of the present invention exhibits excellentanticancer action even when used as a simple agent, its effect can beenhanced by using it in combination with one or more of the concomitantdrugs mentioned above (multi-agent coadministration). As examples ofsaid “hormonal therapeutic agents,” there may be mentioned fosfestrol,diethylstylbestrol, chlorotrianisene, medtoxyprogesterone acetate,megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol,allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene,levormeloxifene, anti-estrogens (e.g., tamoxifen citrate, toremifenecitrate), pill preparations, mepitiostane, testrolactone,aminoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin,leuprorelin), droloxifene, epitiostanol, ethinylestradiol sulfonate,aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole,retrozole, exemestane, vorozole, formestane), anti-androgens (e.g.,flutamide, bicartamide, nilutamide), 5 α-reductase inhibitors (e.g.,finasteride, epristeride), adrenocorticohormone drugs (e.g.,dexamethasone, prednisolone, betamethasone, triamcinolone), androgensynthesis inhibitors (e.g., abiraterone), and retinoid and drugs thatretard retinoid metabolism (e.g., liarozole), etc., and LH-RH agonists(e.g., goserelin acetate, buserelin, leuprorelin) are preferable.

[0210] As examples of said “chemotherapeutic agents”, there may bementioned alkylating agents, antimetabolites antagonists, anticancerantibiotics, and plant-derived anticancer agents.

[0211] As examples of “alkylating agents”, there may be mentionednitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl,cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan,dacarbazine, ranimustine, estramustine phosphate sodium,triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman,etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin,altretamine, ambamustine, dibrospidium hydrochloride, fotemustine,prednimustine, pumitepa, ribomustin, temozolomide, treosulphan,trophosphamide, zinostatin stimalamer, carboquone, adozelesin,cystemustine, and bizelesin.

[0212] As examples of “antimetabolites”, there may be mentionedmercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate,enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride,5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur,gallocitabine, emmitefur), aminopterine, leucovorin calcium, tabloid,butocine, folinate calcium, levofolinate calcium, cladribine, emitefur,fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim,idoxuridine, mitoguazone, thiazophrine, and ambamustine, etc.

[0213] As examples of “anticancer antibiotics”, there may be mentionedactinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3, bleomycinhydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicinhydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride,pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin,mithramycin, sarcomycin, carzinophilin, mitotane, zorubicinhydrochloride, mitoxantrone hydrochloride, and idarubicin hydrochloride,etc.

[0214] As examples of “plant-derived anticancer agents”, there may bementioned etoposide, etoposide phosphate, vinblastine sulfate,vincristine sulfate, vindesine sulfate, teniposide, paclitaxel,docetaxel, and vinorelbine, etc.

[0215] As examples of said “immunotherapeutic agents (BRM)”, there maybe mentioned picibanil, krestin, sizofiran, lentinan, ubenimex,interferons, interleukins, macrophage colony-stimulating factor,granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCGvaccine, Corynebacterium parvum, levamisole, polysaccharide K, andprocodazole.

[0216] The “growth factor” in said “drugs that inhibit the activity ofgrowth factors or growth factor receptors”, there may be mentioned anysubstances that promote cell proliferation, which are normally peptideshaving a molecular weight of not more than 20,000 that are capable ofexhibiting their activity at low concentrations by binding to areceptor, including (1) EGF (epidermal growth factor) or substancespossessing substantially the same activity as it [e.g., EGF, heregulin(HER2 ligand)], (2) insulin or substances possessing substantially thesame activity as it [e.g., insulin, IGF (insulin-like growth factor)-1,IGF-2], (3) FGF (fibroblast growth factor) or substances possessingsubstantially the same activity as it [e.g., acidic FGF, basic FGF, KGF(keratinocyte growth factor), FGF-10, etc.], and (4) other cell growthfactors [e.g., CSF (colony stimulating factor), EPO (erythropoietin),IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derivedgrowth factor), TGFβ (transforming growth factor β), HGF (hepatocytegrowth factor), VEGF (vascular endothelial growth factor)].

[0217] As examples of said “growth factor receptors”, there may bementioned any receptors capable of binding to the aforementioned growthfactors, including EGF receptor, heregulin receptor (HER2), insulinreceptor-1, insulin receptor-2, IGF receptor, FGF receptor-1 or FGFreceptor-2, and the like.

[0218] As examples of said “drugs that inhibit the activity of cellgrowth factor”, there may be mentioned Herceptin (HER2 antibody).

[0219] In addition to the aforementioned drugs, L-asparaginase,aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complexsalt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors (e.g.,irinotecan, topotecan), topoisomerase II inhibitors (e.g., sobuzoxane),differentiation inducers (e.g., retinoid, vitamin D), angiogenesisinhibitors, α-blockers (e.g., tamsulosin hydrochloride), etc. can beused.

[0220] Among those mentioned above, LH-RH agonists (e.g., goserelinacetate, buserelin, leuprorelin), Herceptin (HER2 antibody), etc. arepreferable.

[0221] In combination of the compound of the present invention and thecombination agent of the present invention, the administration time ofthe compound of the present invention and the combination agent is notrestricted, and the compound of the present invention or the combinationagent can be administered to an administration subject simultaneously,or may be administered at different times. The dosage of the combinationagent may be determined according to the administration amountclinically used, and can be appropriately selected depending on anadministration subject, administration route, disease, combination andthe like.

[0222] The administration mode of the compound of the present inventionand the combination agent of the present invention is not particularlyrestricted, and it is sufficient that the compound of the presentinvention and the combination agent are combined in administration.Examples of such administration mode include the following methods:

[0223] (1) The compound of the present invention and the combinationagent are simultaneously produced to give a single preparation which isadministered. (2) The compound of the present invention and thecombination agent are separately produced to give two kinds ofpreparations which are administered simultaneously by the sameadministration route. (3) The compound of the present invention and thecombination agent are separately produced to give two kinds ofpreparations which are administered by the same administration routeonly at the different times. (4) The compound of the present inventionand the combination agent are separately produced to give two kinds ofpreparations which are administered simultaneously by the differentadministration routes. (5) The compound of the present invention and thecombination agent are separately produced to give two kinds ofpreparations which are administered by the different administrationroutes only at different times (for example, the compound of the presentinvention and the combination agent are administered in this order, orin the reverse order). After here, These administration modes arereferred to as the combination agent of the present invention.

[0224] A combination agent of the present invention has low toxicity,and for example, the compound of the present invention or (and) theabove-mentioned combination drug can be mixed, according to a methodknown per se, with a pharmacologically allowable carrier to givepharmaceutical compositions, for example, tablets (including asugar-coated tablet, film-coated tablet), powders, granules, capsules(including a soft capsule), solutions, injections, suppositories,sustained release agents and the like which can be safely administeredorally or parenterally (e.g., local, rectum, vein, and the like). Aninjection can be administered by intravenous, intramuscular,subcutaneous or intraorgan route, or directly to the lesion.

[0225] As the pharmacologically-allowable carrier which may be used inproduction of the combination agent of the present invention, the samethose for the above mentioned pharmaceutical composition of the presentinvention can be used.

[0226] The compounding ratio of the compound of the present invention tothe combination drug in the combination agent of the present inventioncan be appropriately selected depending on an administration subject,administration route, diseases and the like.

[0227] For example, the content of the compound of the present inventionin the combination agent of the present invention differs depending onthe form of a preparation, and usually from about 0.01 to 100% byweight, preferably from about 0.1 to 50% by weight, further preferablyfrom about 0.5 to 20% by weight, based on the preparation.

[0228] The content of the combination drug in the combination agent ofthe present invention differs depending on the form of a preparation,and usually from about 0.01 to 100% by weight, preferably from about 0.1to 50% by weight, further preferably from about 0.5 to 20% by weight,based on the preparation.

[0229] The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to 99.99% by weight,preferably from about 10 to 90% by weight, based on the preparation.

[0230] In the case when the compound of the present invention and thecombination drug are separately prepared respectively, the same contentsmay be adopted.

[0231] These preparations can be produced by a method known per seusually used in a preparation process.

[0232] For example, the compound of the present invention and thecombination drug can be made into an aqueous injection together with adispersing agent (e.g., Tween 80 (manufactured by Atlas Powder, US), HCO60 (manufactured by Nikko Chemicals), polyethylene glycol,carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose,dextrin and the like), a stabilizer (e.g., ascorbic acid, sodiumpyrosulfite, and the like), a surfactant (e.g., Polysorbate 80, macrogoland the like), a solubilizer (e.g., glycerin, ethanol and the like), abuffer (e.g., phosphoric acid and alkali metal salt thereof, citric acidand alkali metal salt thereof, and the like), an isotonizing agent(e.g., sodium chloride, potassium chloride, mannitol, sorbitol, glucoseand the like), a pH regulator (e.g., hydrochloric acid, sodium hydroxideand the like), a preservative (e.g., ethyl p-oxybenzoate, benzoic acid,methylparaben, propylparaben, benzyl alcohol and the like), a dissolvingagent (e.g., conc. glycerin, meglumine and the like), a dissolution aid(e.g., propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like), and the like, or can bedissolved, suspended or emulsified in a vegetable oil such as olive oil,sesame oil, cotton seed oil, corn oil and the like or a dissolution aidsuch as propylene glycol and molded into an oily injection.

[0233] In the case of a preparation for oral administration, anexcipient (e.g., lactose, sucrose, starch and the like), adisintegrating agent (e.g., starch, calcium carbonate and the like), abinder (e.g., starch, gum Arabic, carboxymethylcellulose,polyvinylpyrrolidone, hydroxpropylcellulose and the like), a lubricant(e.g., talc, magnesium stearate, polyethylene glycol 6000 and the like)and the like, for example, can be added to the compound of the presentinvention or the combination drug, according to a method known per se,and the mixture can be compression-molded, then if desirable, the molderproduct can be coated by a method known per se for the purpose ofmasking of taste, enteric property or durability, to obtain apreparation for oral administration. As this coating agent, for example,hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,hydroxymethylcellulose stearate succinate, Eudoragit (methacrylic acid,acrylic acid copolymer, manufactured by Rohm, DE), pigment (e.g., ironoxide red, titanium dioxide, et.) and the like can be used. Thepreparation for oral administration may be any of a quick releasepreparation and a sustained release preparation.

[0234] For example, in the case of a suppository, the compound of thepresent invention and the combination drug can be made into an oily oraqueous solid, semisolid or liquid suppository according to a methodknown per ser. As the oily substrate used in the above-mentionedcomposition, for example, glycerides of higher fatty acids [e.g., cacaobutter, Witebsols (manufactured by Dynamite Novel, DE), etc.],intermediate grade fatty acids [e.g., Myglyols (manufactured by DynamiteNovel, DE), etc.], or vegetable oils (e.g., sesame oil, soy bean oil,cotton seed oil and the like), and the like are listed. Further, as theaqueous substrate, for example, polyethylene glycols, propylene glycolare listed, and as the aqueous gel substrate, for example, natural gums,cellulose derivatives, vinyl polymers, acrylic acid polymers and thelike are listed.

[0235] As the above-mentioned sustained release agent, sustained releasemicrocapsules and the like are listed.

[0236] For obtaining a sustained release microcapsule, a method knownper se can be adopted, and for example, it is preferably molded into asustained release preparation shown in the following [2] beforeadministration.

[0237] A compound of the present invention is preferably molded into anoral administration preparation such as a solid preparation (e.g.,powder, granule, tablet, capsule) and the like, or molded into a rectumadministration preparation such as a suppository. Particularly, an oraladministration preparation is preferable.

[0238] The combination drug can e made into the above-mentioned drugform depending on the kind of the drug.

[0239] [1] An injection of the compound of the present invention or thecombination drug, and preparation thereof, [2] a sustained releasepreparation or quick release preparation of the compound of the presentinvention or the combination drug, and preparation thereof, [3] asublingual, buccal or intraoral quick integrating agent of the compoundof the present invention or the combination drug, and preparationthereof, will be described below specifically.

[0240] [1] Injection and Preparation Thereof

[0241] An injection prepared by dissolving the compound of the presentinvention or the combination drug into water is preferable. Thisinjection may be allowed to contain a benzoate and/or salicylate.

[0242] The injection is obtained by dissolving the compound of thepresent invention or the combination drug, and if desirable, a benzoateand/or salicylate, into water.

[0243] As the above-mentioned salts of benzoic acid and salicylic acid,for example, salts of alkali metals such as sodium, potassium and thelike, salts of alkaline earth metals such as calcium, magnesium and thelike, ammonium salts, meglumine salts, organic acid salts such astromethamol and the like, etc. are listed.

[0244] The concentration of the compound of the present invention or thecombination drug in an injection is from 0.5 to 50 w/v %, preferablyfrom about 3 to 20 w/v %. The concentration of a benzoate salt or/andsalicylate salt is from 0.5 to 50 w/v %, preferably from 3 to 20 w/v %.

[0245] Into a preparation of the present invention, additives usuallyused in an injection, for example, a stabilizer (ascorbic acid, sodiumpyrosulfite, and the like), a surfactant (Polysorbate 80, macrogol andthe like), a solubilizer (glycerin, ethanol and the like), a buffer(phosphoric acid and alkali metal salt thereof, citric acid and alkalimetal salt thereof, and the like), an isotonizing agent (sodiumchloride, potassium chloride, and the like), a dispersing agent(hydroxypropylmethylcellulose, dextrin), a pH regulator (hydrochloricacid, sodium hydroxide and the like), a preservative (ethylp-oxybenzoate, benzoic acid and the like), a dissolving agent (conc.glycerin, meglumine and the like), a dissolution aid (propylene glycol,sucrose and the like), a soothing agent (glucose, benzyl alcohol and thelike), and the like, can be appropriately compounded. These additivesare generally compounded in a proportion usually used in an injection.

[0246] It is advantageous that pH of an injection is controlled from 2to 12, preferably from 2.5 to 8.0 by addition of a pH regulator.

[0247] An injection is obtained by dissolving the compound of thepresent invention or the combination drug and if desirable, a benzoateand/or a salicylate, and if necessary, the above-mentioned additivesinto water. These may be dissolved in any order, and can beappropriately dissolved in the same manner as in a conventional methodof producing an injection.

[0248] An aqueous solution for injection may be advantageously beheated, alternatively, for example, filter sterilization, high pressureheat sterilization and the like can be conducted in the same manner asfor a usual injection, to provide an injection.

[0249] It may be advantageous that an aqueous solution for injection issubjected to high pressure heat sterilization at 100 to 121° C. for 5 to30 minutes.

[0250] Further, a preparation endowed with an antibacterial property ofa solution may also be produced so that it can be used as a preparationwhich is divided and administered multiple-times.

[0251] [2] Sustained Release Preparation or Quick Release Preparation,and Preparation Thereof

[0252] A sustained release preparation is preferable which is obtained,if desirable, by coating a nucleus containing the compound of thepresent invention or the combination drug with a film agent such as awater-insoluble substance, swellable polymer and the like. For example,a sustained release preparation for oral administration of onceadministration per day type is preferable.

[0253] As the water-insoluble substance used in a film agent, there arelisted, for example, cellulose ethers such as ethylcellulose,butylcellulose ad the like, cellulose esters such as cellulose stearate,cellulose propionate and the like, polyvinyl esters such as polyvinylacetate, polyvinyl butyrate and the like, acrylic acid/methacrylic acidcopolymers, methyl methacrylate copolymers, ethoxyethylmethacrylate/cinnamoethyl methacryalte/aminoalkyl methacrylatecopolymers, polyacrylic acid, polymethacrylic acid, methacrylic acidalkylamide copolymers, poly(methyl methacrylate), polymethacrylate,polymethacrylamide, aminoalkyl methacryalte copolymers, poly(methacrylicanhydride), glycidyl methacrylate copolymer, particularly, acrylicacid-based polymers such as Eudoragits (Rhom Farma) such as EudoragitRS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acryalte.methylmethacryalte.trimethyl chloride methacryalte.ammoniumethyl copolymer),Eudoragit NE-30D (methyl methacryalte.ethyl acrylate copolymer), and thelike, hardened oils such as hardened castor oil (e.g., Lovery wax(Freunt) and the like), waxes such as carnauba wax, fatty acid glycerinester, paraffin and the like, polyglycerin fatty esters, and the like.

[0254] As the swellable polymer, polymers having an acidic dissociatinggroup and showing pH dependent swell are preferable, and polymersmanifesting small swelling in acidic regions such as in stomach andlarge swelling in neutral regions such as in small intestine and largeintestine are preferable.

[0255] As such a polymer having an acidic dissociating group and showingpH dependent swell, cross-linkable polyacrylic acid copolymers such as,for example, Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil, calcium polycarbophil (last two are manufactured by BFgood rich), Hibiswako 103, 104, 105, 304 (all are manufactured by WakoPurechemical Co., Ltd.), and the like, are listed.

[0256] The film agent used in a sustained release preparation mayfurther contain a hydrophilic substance.

[0257] As the hydrophilic substance, for example, polysaccharides whichmay contain a sulfate group such as pullulan, dextrin, alkali metalalginate and the like, polysaccharides having a hydroxyalkyl group orcarboxyalkyl group such as hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose sodium and thelike, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol and the like.

[0258] The content of a water-insoluble substance in the film agent of asustained release preparation is from about 30 to 90% (w/w), preferablyfrom about 35 to 80% (w/w), further preferably from about 40 to 75%(w/w), the content of a swellable polymer is from about 3 to 30% (w/w),preferably from about 3 to 15% (w/w). The film agent may further containa hydrophilic substance, and in which case, the content of a hydrophilicsubstance in the film agent is about 50% (w/w) or less, preferably about5 to 40% (w/w), further preferably from about 5 to 35% (w/w). This %(w/w) indicates % by weight based on a film agent composition which isobtained by removing a solvent (e.g., water, lower alcohols such asmethanol, ethanol and the like) from a film agent solution.

[0259] The sustained release preparation is produced by preparing anucleus containing a drugs as exemplified below, then, coating theresulted nucleus with a film agent solution prepared by heat-solving awater-insoluble substance, swellable polymer and the like or bydissolving or dispersing it in a solvent.

[0260] I. Preparation of Nucleus Containing Drug

[0261] The form of nucleus containing a drug to be coated with a filmagent (hereinafter, sometimes simply referred to as nucleus) is notparticularly restricted, and preferably, the nucleus is formed intoparticles such as a granule or fine particle.

[0262] When the nucleus is composed of granules or fine particles, theaverage particle size thereof is preferably from about 150 to 2000 μm,further preferably, from about 500 to 1400 μm.

[0263] Preparation of the nucleus can be effected by a usual productionmethod. For example, a suitable excipient, binding agent, integratingagent, lubricant, stabilizer and the like are mixed into a drug, and themixture is subjected to a wet extrusion granulating method, fluidizedbed granulating method or the like, to prepare a nucleus.

[0264] The content of drugs in a nucleus is from about 0.5 to 95% (w/w),preferably from about 5.0 to 80% (w/w), further preferably from about 30to 70% (w/w).

[0265] As the excipient contained in the nucleus, for example,saccharides such as sucrose, lactose, mannitol, glucose and the like,starch, crystalline cellulose, calcium phosphate, corn starch and thelike a reused. Among them, crystalline cellulose, corn starch arepreferable.

[0266] As the bonder, for example, polyvinyl alcohol, hydroxypropylcellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gumArabic, gelatin, starch and the like are used. As the disintegratingagent, for example, carboxymethylcelulose calcium (ECG505),crosscarmelose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone(Crosspovidone), lower substitution hydroxypropylcellulose (L-HPC) andthe like are used. Among them, hydroxypropylcellulose,polyvinylpyrrolidone, lower substitution hydroxypropylcellulose arepreferable. As the lubricant and coagulation inhibitor, for example,talc, magnesium stearate and inorganic salts thereof are used, and asthe lubricant, polyethylene glycol and the like are used. As thestabilizer, acids such as tartaric acid, citric acid, succinic acid,fumaric acid, maleic acid and the like, are used.

[0267] A nucleus can also be prepared by, in addition to theabove-mentioned, for example, a rolling granulation method in which adrug or a mixture of a drug with an excipient, lubricant and the like isadded portionwise onto an inert carrier particle which is the core ofthe nucleus while spraying a binder dissolved in a suitable solvent suchas water, lower alcohol (e.g., methanol, ethanol and the like) and thelike, a pan coating method, a fluidized bed coating method or a meltgranulating method. As the inert carrier particle, for example, thosemade of sucrose, lactose, starch, crystalline cellulose, waxes can beused, and the average particle size thereof is preferably from about 100μm to 1500 μm.

[0268] For separating a drug and a film agent contained in a nucleus,the surface of the nucleus may be coated with a protective agent. As theprotective agent, for example, the above-mentioned hydrophilicsubstances, water-insoluble substances and the like are used. As theprotective agent, preferably polyethylene glycol, and polysaccharideshaving a hydroxyalkyl group or carboxyalkyl group are used, morepreferably, hydroxypropylmethylcellulose and hydroxypropyplcellulose areuse. The protective agent may contain, as astabilizer, acids such astartaric acid, citric acid, succinic acid, fumaric acid, maleic acid andthe like, and lubricants such as talc and the like. When the protectiveagent is used, the coating amount is from about 1 to 15% (w/w),preferably from about 1 to 10% (w/w), further preferably from about 2 to8% (w/w), based on the nucleus.

[0269] The protective agent can be coated by a usual coating method, andspecifically, the protective agent can be coated, for example, by afluidized bed coating method, pan coating method and the like.

[0270] II. Coating of Nucleus with Film Agent

[0271] A nucleus obtained in the above-mentioned step I is coated with afilm agent solution obtained by heat-solving the above-mentionedwater-insoluble substance and pH-dependent swellable polymer, and ahydrophilic substance, or by dissolving or dispersing them in a solvent,to give a sustained release preparation.

[0272] As the method for coating a nucleus with a film agent solution,for example, a spray coating method and the like are listed.

[0273] The composition ratio of a water-insoluble substance, swellablepolymer and hydrophilic substance in a film agent solution isappropriately selected so that the contents of these components in acoated film are the above-mentioned contents, respectively.

[0274] The coating amount of a film agent is from about 1 to 90% (w/w),preferably from about 5 to 50% (w/w), further preferably from about 5 to35% (w/w), based on a nucleus (not including coating amount ofprotective agent).

[0275] As the solvent in a film agent solution, water or an organicsolvent can be used alone or in admixture thereof. In the case of use inadmixture, the mixing ratio of water to an organic solvent(water/organic solvent: by weight) can be varied in the range from 1 t100%, and preferably from 1 to about 30%. The organic solvent is notparticularly restricted providing it dissolves a water-insolublesubstance, and for example, lower alcohols such as methyl alcohol, ethylalcohol, isopropyl alcohol, n-butyl alcohol and the like, lower alkanonesuch as acetone and the like, acetonitrile, chloroform, methylenechloride and the like are used. Among them, lower alcohols arepreferable, and ethyl alcohol and isopropyl alcohol are particularlypreferable. Water, and a mixture of water with an organic solvent arepreferably used as a solvent for a film agent. In this case, ifnecessary, an acid such as tartaric acid, citric acid, succinic acid,fumaric acid, maleic acid and the like may also be added into a filmagent solution for stabilizing the film agent solution.

[0276] An operation of coating by spray coating can be effected by ausual coating method, and specifically, it can be effected byspray-coating a film agent solution onto a nucleus by a fluidized bedcoating method, pan coating method and the like. In this case, ifnecessary, talc, titanium oxide, magnesium stearate, calcium stearate,light anhydrous silicic acid and the like may also be added as alubricant, and glycerin fatty ester, hardened castor oil, triethylcitrate, cetyl alcohol, stearyl alcohol and the like may also be addedas a plasticizer.

[0277] After coating with a film agent, if necessary, an antistaticagent such as talc and the like may be mixed.

[0278] The quick release preparation may be liquid (solution,suspension, emulsion and the like) or solid (particle, pill, tablet andthe like). Oral agents and parenteral agents such as an injection andthe like are used, and oral agents are preferable.

[0279] The quick release preparation, usually, may contain, in additionto an active component drug, also carriers, additives and excipientsconventionally used in the production field (hereinafter, sometimesabbreviated as excipient). The preparation excipient used is notparticularly restricted providing it is an excipient ordinarily used asa preparation excipient. For example, as the exipient for an oral solidpreparation, lactose, starch, corn starch, crystalline cellulose (AcevilPH101, manufactured by Asahi Chemical Industry Co., Ltd., and the like),powder sugar, granulated sugar, mannitol, light anhydrous silicic acid,magnesium carbonate, calcium carbonate, L-cysteine and the like arelisted, and preferably, corn starch and mannitol and the like arelisted. These excipients can be used alone or in combination of two ormore. The content of the excipient is, for example, from about 4.5 to99.4 w/w %, preferably from about 20 to 98.5 w/w %, further preferablyfrom about 30 to 97 w/w %, based on the total amount of the quickrelease preparation.

[0280] The content of a drug in the quick release preparation can beappropriately selected in the range from about 0.5 to 95%, preferablyfrom about 1 to 60% based on the total amount of the quick releasepreparation.

[0281] When the quick release preparation is an oral solid preparation,it usually contains, in addition to the above-mentioned components, alsoan integrating agent. As this integrating agent, there are used, forexample, carboxymethylcellulose calcium (ECG-505, manufactured by GotokuYakuhin), crosscarmelose sodium (for example, Actisol, manufactured byAsahi Chemical Industry Co., Ltd.), crosspovidone (for example, ColiconeCL, manufactured by BASF), lower substitution hydroxypropylcellulose(manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch(manufactured by Matsutani Kagaku K.K.), carboxymethylstarch sodium(Exprotab, manufactured by Kimura Sangyo), partially α-nized starch(PCS, manufactured by Asahi Chemical Industry Co., Ltd.), and the likeare used, and for example, those which disintegrate a granule byadsorbing water in contact with water, causing swelling, or making achannel between an effective ingredient constituting the nucleus and anexcipient, can be used. These disintegrating agents can be used alone orin combination of two or more. The amount of the disintegrating agentused is appropriately selected depending on the kind and compoundingamount of a drug used, design of releasing property, and the like, andfor example, from about 0.05 to 30 w/w %, preferably from about 0.5 to15 w/w %, based on the total amount of the quick releasing agent.

[0282] When the quick release preparation is an oral solid preparation,it may further contain, in addition to the above-mentioned composition,if desired, additives conventional in solid preparations. As such anadditive, there are used, for example, a binder (e.g., sucrose, gelatin,gum Arabic powder, methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcelllulose, carboxylmethylcellulose,polybinylpyrrolidone, pluran, dextrin and the like), a lubricant (e.g.,polyethylene glycol, magnesium stearate, talc, light anhydrous silicicacid (for example, aerosil (Nippon Aerosil)), a surfactant (e.g.,anionic surfactants such as sodium alkylsulfate and the like, nonionicsurfactants such as polyoxyethylene fatty acid ester and polyoxyethylenesorbitan fatty acid ester, polyoxyethylene cartor oil derivatives andthe like), a coloring agent (e.g., tar coloring matter, caramel, ironoxide red, titanium oxide, riboflavins), if necessary, an appetizingagent (e.g., sweetening agent, arom and the like), an adsorbent,preservative, wetting agent,.antistatic agent, and the like. Further, asthe stabilizer, an organic acid such as tartaric acid, citric acid,succinic acid, fumaric acid and the like may also be added.

[0283] As the above-mentioned binder, hydroxypropylcellulose,polyethylene glycol and polyvinylpyrrolidone and the like are preferablyused.

[0284] The quick releasing reparation can be prepared by, based on ausual technology of producing preparations, mixing the above-mentionedcomponents, and if necessary, further kneading the mixture, and moldingit. The above-mentioned mixing is conducted by generally used methods,for example, mixing, kneading and the like. Specifically, when a quickrelease preparation is formed, for example, into a particle, it can beprepared, according to the same means as in the above-mentioned methodfor preparing a nucleus of a sustained release preparation, by mixingthe components using a vertical granulator, universal kneader(manufactured by Hata Tekkosho), fluidized bed granulator FD-5S(manufactured by Pulek), and the like, then, subjecting the mixture to awet extrusion granulation method, fluidized bed granulation method andthe like.

[0285] Thus obtained quick releasing preparation and sustained releasingpreparation may be themselves made into products or made into productsappropriately together with preparation excipients and the like,separately, by an ordinary method, then, may be administeredsimultaneously or may be administered in combination at anyadministration interval, or they may be themselves made into one oralpreparation (e.g., granule, fine particle, tablet, capsule and the like)or made into one oral preparation together with preparation excipientsand the like. It may also be permissible that they are made intogranules or fine particles, and filled in the same capsule to be used asa preparation for oral administration.

[0286] [3] Sublinguial, Buccal or Intraoral Quick Disintegrating Agentand Preparation Thereof

[0287] Sublinguial, buccal or intraoral quick disintegrating agents maybe a solid preparation such as tablet and the like, or may be an oralmucosa membrane patch (film).

[0288] As the sublinguial, buccal or intraoral quick disintegratingagent, a preparation containing the compound of the present invention orthe combination drug and an excipient is preferable. It may contain alsoauxiliary agents such as a lubricant, isotonizing agent, hydrophiliccarrier, water-dispersible polymer, stabilizer and the like. Further,for easy absorption and increase in in vivo use efficiency,β-cyclodextrin or β-cyclodextrin derivatives (e.g.,hydroxypropyl-β-cyclodextrin and the like) and the like may also becontained.

[0289] As the above-mentioned excipient, lactose, sucrose, D-mannitol,starch, crystalline cellulose, light anhydrous silicic acid and the likeare listed. As the lubricant, magnesium stearate, calcium stearate,talc, colloidal silica and the like are listed, and particularly,magnesium stearate and colloidal silica are preferable. As theisotonizing agent, sodium chloride, glucose, fructose, mannitol,sorbitol, lactose, saccharose, glycerin, urea and the like are listed,and particularly, mannitol is preferable. As the hydrophilic carrier,swellable hydrophilic carriers such as crystalline cellulose,ethylcellulose, crosslinkable polyvinylpyrrolidone, light anhydroussilicic acid, silicic acid, dicalcium phosphate, calcium carbonate andthe like are listed, and particularly, crystalline cellulose (e.g., finecrystalline cellulose and the like) is preferable. As thewater-dispersible polymer, gums (e.g., gum tragacanth, acacia gum,cyamoposis gum), alginates (e.g., sodium alginate), cellulosederivatives (e.g., methylcellulose, carboxymethylcellulose,hydroxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose), gelatin, water-soluble starch,polyacrylic acids (e.g., Carbomer), polymethacylic acid, polyvinylalcohol, plyethylene glycol, polyvinylpyrrolicone, polycarbofil,ascorbate palmitates and the like are listed, andhydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like are preferable. Particularly, hydroxypropylmethylcellulose ispreferable. As the stabilizer, cysteine, thiosorbitol, tartaric acid,citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfiteand the like are listed, and particularly, citric acid and ascorbic acidare preferable.

[0290] The sublinguial, buccal or intraoral quick disintegrating agentcan be produced by mixing the compound of the present invention or thecombination drug and an excipient by a method known per se. Further, isdesirable, auxiliary agents such as a lubricant, isotonizing agent,hydrophilic carrier, water-dispersible polymer, stabilizer, coloringagent, sweetening agent, preservative and the like may be mixed. Thesublingual, buccal or intraoral quick disintegrating agent is obtainedby mixing the above-mentioned components simultaneously or at a timeinterval, then subjecting the mixture to tablet-making molding underpressure. For obtaining suitable hardness, it may also be permissiblethat the materials are moistened by using a solvent such as water,alcohol and the like if desired before and after the tablet makingprocess, and after the molding, the materials are dried, to obtain aproduct.

[0291] In the case of molding into a mucosa membrane patch (film), thecompound of the present invention or the combination drug and theabove-mentioned water-dispersible polymer (preferably,hydroxypropylcellulose, hydroxypropylmethylcellulose), excipient and thelike are dissolved in a solvent such as water and the like, and theresulted solution is cast, to give a film. Further, additives such as aplasticizer, stabilizer, antioxidant, preservative, coloring agent,buffer, sweetening agent and the like may also be added. For impartingsuitable elasticity to the film, glycols such as polyethylene glycol,propylene glycol and the like may be contained, or for enhancingadhesion of the film to an intraoral mucosa membrane lining, abio-adhesive polymer (e.g., polycarbofil, carbopol) may also becontained. In the casting, a solution is poured on the non-adhesivesurface, spread to uniform thickness (preferably, about 10 to 1000micron) by an application tool such as a doctor blade and the like,then, the solution is dried to form a film. It may be advantageous thatthus formed film is dried at room temperature or under heat, and cutinto given area.

[0292] As the preferable intraoral quick disintegrating agent, there arelisted solid quick scattering dose agents composed of a network bodycomprising the compound of the present invention or the combinationdrug, and a water-soluble or water-diffusible carrier which is inert tothe compound of the present invention or combination drug, are listed.This network body is obtained by sublimating a solvent from the solidcomposition constituted of a solution prepared by dissolving thecompound of the present invention or the combination drug in a suitablesolvent.

[0293] It is preferable that the composition of an intraoral quickdisintegrating agent contains a matrix forming agent and a secondarycomponent, in addition to the compound of the present invention or thecombination drug.

[0294] Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins and, soybean, wheat andpsyllium seed protein and the like; rubber substances such as gumArabic, guar gum, agar, xathane gum and the like; polysaccharides;alginic acids; carboxymethylcelluloses; carageenans; dextrans; pectines;systhetic polymers such as polyvinylpyrrolidone and the like; substancesderived from a gelatin-gum Arabic complex, and the like. Further,saccharides such as mannitol, dextrose, lactose, galactose, trehaloseand the like; cyclic saccharides such as cyclodextrin and the like;inorganic salts such as sodium phosphate, sodium chloride and aluminumsilicate and the like; amino acids having 2 to 12 carbon atoms such asglycine, L-alanine, L-asparatic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine and the like, are contained.

[0295] One or more of the matrix forming agents can be introduced in asolution or suspension before solidification. Such as matrix formingagent may be present in addition to a surfactant, or may be presentwhile a surfactant being excluded. The matrix forming agent aids tomaintain the compound of the present invention or the combination drugin the solution or suspension in diffused condition, in addition toformation of the matrix.

[0296] The composition may contain secondary components such as apreservative, antioxidant, surfactant, thickening agent, coloring agent,pH controlling agent, flavoring agent, sweetening agent, food tastemasking agent and the like. As the suitable coloring agent, there arelisted red, black and yellow iron oxides, and FD & C dyes such as FD & CBlue 2, FD & C Red 40 and the like manufactured by Elis and Eberald.Examples of the suitable flavoring agent include mint, raspberry,licorice, orange, lemon, grape fruit, caramel, vanilla, cherry, grapeflavor and combinations thereof. Examples of the suitable pH controllingagent include citric acid, tartaric acid, phosphoric acid, hydrochloricacid and maleic acid. Examples of the suitable sweetening agent includeaspartame, acesulfame K and thaumatin and the like. Examples of thesuitable food taste masking agent include sodium bicarbonate, ionexchange resin, cyclodextrin-containing compounds, adsorbent substancesand microcapsulated apomorphine.

[0297] The preparation contains the compound of the present invention orthe combination drug in an amount usually from about 0.1 to 50% byweight, preferably from about 0.1 to 30% by weight, and preferable arepreparations (such as the above-mentioned sublingual agent, buccal andthe like) which can dissolve 90% or more the compound of the presentinvention or the combination drug (into water) within the time range ofabout 1 to 60 minutes, preferably of about 1 to 16 minutes, morepreferably of about 2 to 5 minutes, and intraoral quick disintegratingpreparations which are disintegrated within the range of 1 to 60seconds, preferably of 1 to 30 seconds, further preferably of 1 to 10seconds after place in an oral cavity.

[0298] The content of the above-mentioned exipient in the wholepreparation is from about 10 to 99% by weight, preferably from about 30to 90% by weight. The content of β-cyclodextrin or β-cyclodextrinderivative in the whole preparation is from 0 to about 30% by weight.The content of the lubricant in the whole preparation is from about 0.01to 10% by weight, preferably from about 1 to 5% by weight. The contentof the isotonizing agent in the whole preparation is from about 0.1 to90% by weight, preferably, from about 10 to 70% by weight. The contentof the hydrophilic carrier agent in the whole preparation is from about0.1 to 50% by weight, preferably, from about 10 to 30% by weight. Thecontent of the water-dispersible polymer in the whole preparation isfrom about 0.1 to 30% by weight, preferably, from about 10 to 25% byweight. The content of the stabilizer in the whole preparation is fromabout 0.1 to 10% by weight, preferably, from about 1 to 5% by weight.The above-mentioned preparation may further contain additives such as acoloring agent, sweetening agent, preservative and the like, ifnecessary.

[0299] The dosage of a combination agent of the present inventiondiffers depending on the kind of a compound (I), age, body weight,condition, drug form, administration method, administration period andthe like, and for example, for one sepsis patient (adult, body weight:about 60 kg), the combination agent is administer intravenously, at adose of about 0.01 to 1000 mg/kg/day, preferably about 0.01 to 100mg/kg/day, more preferably about 0.1 to 100 mg/kg/day, particularlyabout 0.1 to 50 mg/kg/day, especially about 1.5 to 30 mg/kg/day, interms of the compound of the present invention or the combination drug,respectively, once or several time in division a day. Of course, sincethe dose as described above varies depending on various conditions,amounts smaller than the above-mentioned dosage may sometimes besufficient, further, amounts over that range sometimes have to beadministered.

[0300] The amount of the combination drug can be set at any value unlessside effects are problematical. The daily dosage in terms of thecombination drug differs depending on the severity, age, sex, bodyweight, sensitivity difference of the subject, administration period,interval, and nature, pharmacy, kind of the pharmaceutical preparation,kind of effective ingredient, and the like, and not particularlyrestricted, and the amount of a drug is, in the case of oraladministration for example, usually from about 0.001 to 2000 mg,preferably from about 0.01 to 500 mg, further preferably from about 0.1to 100 mg, per 1 kg of a mammal and this is usually administered once to4-times in division a day.

[0301] In administration of a medicine of the present invention, thecompound of the present invention may be administered afteradministration of the combination drug or the combination drug may beadministered after administration of the compound of the presentinvention, though they may be administered simultaneously. Whenadministered at a time interval, the interval differs depending on theeffective ingredient, drug form and administration method, and forexample, when the combination drug is administered first, a method inwhich the compound of the present invention is administered within timerange of from 1 minute to 3 days, preferably from 10 minutes to 1 day,more preferably from 15 minutes to 1 hour after administration of thecombination drug is exemplified. When the compound of the presentinvention is administered first, a method in which the combination drugis administered within time range of from 1 minute to 1 day, preferablyfrom 10 minutes to 6 hours, more preferably from 15 minutes to 1 hourafter administration of the compound of the present invention isexemplified.

[0302] In a preferable administration method, for example, thecombination drug which has been formed into an oral administrationpreparation is administered orally at a daily dose of about 0.001 to 200mg/kg, and 15 minutes after, the compound of the present invention whichhas been formed into an oral administration preparation is administeredorally at a daily dose of about 0.005 to 100 mg/kg.

[0303] In addition, the pharmaceutical composition of the presentinvention and the combined agent of the present invention can becombined with a non-drug therapy such as (1) surgery, (2) hypertensivechemotherapy using angiotensin II etc., (3) genetherapy, (4)thermotherapy, (5) cryotherapy, (6) laser cauterization, (7)radiotherapy, etc.

[0304] For example, the pharmaceutical composition of the presentinvention and the combined agent of the present invention inhibits anexpression of resistance, extend disease-free survival, suppressescancer metastasis or recurrence, prolongs survival and provides otherbenefits when used before or after the surgery, etc., or a combinationtreatment comprising 2 or 3 of these therapies.

[0305] Also, treatment with the pharmaceutical composition of thepresent invention and the combined agent of the present invention can becombined with supportive therapies [e.g., (i) administration ofantibiotics (e.g., β-lactams such as pansporin, macrolides such asclarytheromycin) to an combined expression of various infectiousdiseases, (ii) total parentral nutrition, administration of amino acidpreparations and general vitamin preparations for improvement ofmalnutrition, (iii) morphine administration for pain mitigation, (iv)administration of drugs which mitigate adverse reactions such as nausea,vimoting, anorexia, diarrhea, leukopenia, thrombocytopenia, hemoglobinconcentration reduction, hair loss, hepatopathy, renopathy, DIC andfever], (v) administration of drugs for inhibition of multiple drugresistance in cancer].

[0306] Preferably, the pharmaceutical composition of the presentinvention or the combined agent of the present invention is administeredorally (including sustained-release preparations), intravenously(including boluses, infusions and clathrates), subcutaneously andintramuscularly (including boluses, infusions and sustained-releasepreparations), transdermally, intratumorally or proximally before orafter the above-described treatment is conducted.

[0307] As a period for administering the pharmaceutical composition ofthe present invention or the combined agent of the present inventionbefore the surgery, etc., for example, it can be administrated 1-timeabout 30 minutes to 24 hours before the surgery, etc., or in 1 to 3cycles about 3 months to 6 months before the surgery, etc. In this way,the surgery, etc. can be conducted easily because, for example, a cancertissue would be reduced by administering the pharmaceutical compositionof the present invention or the combined agent of the present inventionbefore the surgery, etc. As a period for administering thepharmaceutical composition of the present invention or the combinedagent of the present invention after the surgery, etc., for example, itcan be administrated repeatedly per a few weeks to 3 months, about 30minutes to 24 hours after the surgery, etc. In this way, it makes aneffect of the surgery, etc. increasing by administering thepharmaceutical composition of the present invention or the combinedagent of the present invention after the surgery, etc. Best Mode forCarrying out of the Invention

[0308] The present invention is hereinafter described in detail by meansof, but is not limited to, the following reference examples, workingexamples, preparation examples and test examples.

[0309] In the Reference Examples and Examples, column chromatography wasconducted with observation by TLC (thin layer chromatography). In TLCobservation, the TLC plate used was the Merck Kieselgel 60F₂₅₄ plate,the developing solvent used was the solvent used as the eluent forcolumn chromatography, and the means of detection used was an UVdetector. The silica gel for the column chromatography was also MerckKieselgel 60F₂₅₄ (70-230 mesh). NMR spectra are shown by proton NMR withtetramethylsilane as the internal standard, using VARIAN Gemini-200 (200MHz type spectrometer); δ values are expressed in ppm.

[0310] The abbreviations used in the Reference Examples and Examples aredefined as follows:

[0311] s: Singlet

[0312] br: Broad

[0313] d: Doublet

[0314] t: Triplet

[0315] q: Quartet

[0316] dd: Double doublet

[0317] dt: Double triplet

[0318] m: Multiplet

[0319] J: Coupling constant

[0320] Hz: Hertz

[0321] DMF: N,N-dimethylformamide

[0322] THF: Tetrahydrofuran

WORKING EXAMPLE REFERENCE EXAMPLE 1

[0323] 4-chloromethyl-2-[(E)-2-(4-methylphenyl)ethenyl]-1,3-oxazole

[0324] (i) (E)-3-(4-methylphenyl)-2-propenamide

[0325] To a solution of 4-methylcinnamic acid (15.19 g) in THF (100 ml),DMF (5 drops) was added; under ice cooling, oxalyl chloride (9.6 ml) wasadded, followed by stirring at room temperature for 2 hours. Afteroxalyl chloride (4.0 ml) was added, the reaction mixture was stirred atroom temperature for 1 hour, after which it was concentrated to dryness.The residue was dissolved in ethyl acetate (50 ml); under ice cooling,this solution was added drop by drop to a mixture of 25% aqueous ammonia(50 ml)-ethyl acetate (20 ml). The water layer was salted out; theorganic layer was extracted with ethyl acetate. The extract was driedover magnesium sulfate, after which it was concentrated under reducedpressure. The precipitate was washed with hexane and diethyl ether toyield the titled compound (11.63 g) as colorless crystals.

[0326]¹H-NMR (CDCl₃) δ: 2.37 (3H, s), 5.56 (2H, brs), 6.41 (1H, d,J=15.8), 7.18 (2H, d, J=8.0), 7.42 (2H, d, J=8.0), 7.62 (1H, d, J=15.8).

[0327] IR (KBr): 1671, 1601, 1518, 1397, 1254, 1123, 990, 816 cm⁻¹.

[0328] (ii) 4-chloromethyl-2-[(E)-2-(4-methylphenyl)ethenyl]-1,3-oxazole

[0329] A mixture of (E)-3-(4-methylphenyl)-2-propenamide (8.06 g) and1,3-dichloroacetone (6.98 g) in toluene (50 ml) were refluxed for 3hours. After cooling, the reaction mixture was diluted with ethylacetate, washed with water and saline, and dried over magnesium sulfate,then concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluent: ethyl acetate-hexane=1:4) toyield the titled compound (8.44 g) as a white crystalline powder.

[0330]¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 4.54 (2H, s), 6.87 (1H, d,J=16.2), 7.20 (2H, d, J=8.2), 7.43 (2H, d, J=8.2), 7.52 (1H, d, J=16.2),7.62 (1H, s).

[0331] IR (KBr): 1642, 1607, 1591, 1537, 1345, 1267, 976, 943, 810 cm⁻¹.

REFERENCE EXAMPLE 2

[0332] 4-chloromethyl-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole

[0333] 4-fluorocinnamic acid (25 g) was suspended in dichloromethane(300 ml); under ice cooling and stirring, DMF (0.5 ml) and then oxalylchloride (15.36 ml) were added drop by drop; the same temperature waskept for 3 hours and gradually returned to room temperature. Underreduced pressure, the solvent was distilled off; the residue wasdissolved in ethyl acetate (100 ml). This solution was added drop bydrop to an ice-cooled mixed solution of 25% aqueous ammonia (250 ml) andethyl acetate (52.5 ml). The reaction mixture was extracted with ethylacetate (400 ml×2) and washed with saturated saline, after which it wasdried over anhydrous magnesium sulfate. Under reduced pressure, thesolvent was distilled off; the precipitated crystal was collected byfiltration and dried to yield (E)-3-(4-fluorophenyl)-2-propenamide (24.4g).

[0334] The (E)-3-(4-fluorophenyl)-2-propenamide (17.55 g) thus obtainedand 1,3-dichloroacetone (12.85 g) were molten at 130° C. and stirred for1.5 hours. After the reaction mixture was cooled to room temperature andextracted with ethyl acetate, it was washed with ice water, saturatedaqueous sodium bicarbonate, and saturated saline. After drying withanhydrous sodium sulfate, the solvent was distilled off; the residue waspurified by column chromatography (eluent: diethylether-hexane=1:9→3:17) to yield the titled compound (10.5 g) ascolorless crystals.

[0335]¹H-NMR (CDCl₃) δ: 4.54 (2H, s), 6.84 (1H, d, J=16.0 Hz), 7.09 (2H,t, J=8.8 Hz), 7.47-7.55 (3H, m), 7.63 (1H, s).

[0336] IR (KBr): 3173, 3133, 3063, 3040, 1645, 1601, 1591, 1537, 1508,1435, 1416, 1350, 1275, 1233, 1167, 1101, 999 cm⁻¹.

REFERENCE EXAMPLE 3

[0337]4-chloromethyl-2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazole

[0338] (i) (E)-3-(4-trifluoromethylphenyl)-2-propenamide

[0339] To a suspension of 4-trifluoromethylcinnamic acid (19.4 g) andDMF (6 drops) in THF (100 ml), oxalyl chloride (11.7 ml) was added dropby drop at 0° C., followed by stirring at room temperature for 2 hours.After the solvent was distilled off under reduced pressure, the residuewas dissolved in ethyl acetate (60 ml) and poured into a mixture of 25%aqueous ammonia-ethyl acetate (5:1, 120 ml). After salting-out, thewater layer was extracted with a mixture of ethyl acetate-THF (12:1)(650 ml) and ethyl acetate (100 ml×2) and dried over anhydrous magnesiumsulfate. After the solvent was distilled off under reduced pressure, theresidue was recrystallized from ethyl acetate-hexane to yield the titledcompound (18.0 g) as a colorless tabular crystal.

[0340]¹H-NMR (CDCl₃) δ: 5.58 (2H, br s), 6.53 (1H, d, J=15.8 Hz),7.63-7.72 (5H, m).

[0341] IR (KBr): 3326, 3167, 1686, 1636, 1617, 1404, 1190 cm⁻¹.

[0342] (ii)4-chloromethyl-2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazole

[0343] A solution of (E)-3-(4-trifluoromethylphenyl)-2-propenamide (17.9g) and 1,3-dichloroacetone (14.8 g) in toluene (83 ml) was refluxedunder heating for 9 hours using a Dean-Stark apparatus. After cooling,water was added; the reaction mixture was extracted with ethyl acetateand washed with saturated saline, after which it was dried overanhydrous magnesium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel columnchromatography (eluent: hexane-methyl acetate=6:1→5:1) to yield thetitled compound (15.1 g) as a colorless needle crystal.

[0344]¹H-NMR (CDCl₃) δ: 4.55 (2H, d, J=0.8 Hz), 7.00 (1H, d, J=16.2 Hz),7.56 (1H, d, J=16.2 Hz), 7.64-7.68 (5H, m).

[0345] IR (KBr): 1350, 1325, 1170, 1136, 1113, 1071, 959, 826, 727, 708cm⁻¹.

REFERENCE EXAMPLE 4

[0346] 4-chloromethyl-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole

[0347] Using (E)-3-(2,4-difluorophenyl)-2-propenamide (9.16 g) and1,3-dichloroacetone (7.62 g), the same reaction as Reference Example1-(ii) was carried out to yield the titled compound (6.31 g) ascolorless crystals.

[0348]¹H-NMR (CDCl₃) δ: 4.55 (2H, s), 6.8-7.0 (2H, m), 6.96 (1H, d,J=16.8), 7.45-7.7 (3H, m).

REFERENCE EXAMPLE 5

[0349] 4-chloromethyl-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole

[0350] Using (E)-(2,6-difluorophenyl)-2-propenamide (9.0 g) and1,3-dichloroacetone (7.49 g), the same reaction as Reference-Example1-(ii) was carried out to yield the titled compound (7.18 g) as alight-yellow solid.

[0351]¹H-NMR (CDCl₃) δ: 4.55 (2H, s), 6.85-7.0 (2H, m), 7.2-7.35 (2H,m), 7.55-7.7 (1H, m), 7.66 (1H, s).

REFERENCE EXAMPLE 6

[0352] 3-(1H-imidazol-2-yl)-1,2-propanediol

[0353] 3,4-dihydroxybutyronitrile (30.33 g) was dissolved in absolutemethanol (12.2 ml); under ice cooling and stirring, a 5.12 N solution ofhydrogen chloride in ether (62 ml) was added under 5° C. The reactionmixture was stirred at constant temperature for 35 hours to yield adouble-layered solution. The upper layer was removed, and the lowerlayer was dissolved in absolute methanol (45 ml). A solution ofaminoacetaldehyde dimethylacetal (31.5 g) in absolute methanol (45 ml)was added under ice cooling and stirring under 20° C., followed bystirring for 27 hours. Under reduced pressure, the solvent was distilledoff; to the residue, water (57 ml) and concentrated hydrochloric acid(142 ml) were added, followed by stirring at room temperature for 2hours. Under reduced pressure, the solvent was distilled off; to theresidue, an aqueous solution of potassium carbonate was added; afteradjustment to pH 10, the solvent was again distilled off. The residuewas extracted with ethanol (500 ml) and concentrated to dryness. Afterpurification by silica gel column chromatography, the concentratedextract was desalinized with an ion exchange resin (Amberlyst 15) toyield the titled compound (13.16 g) as pale-brown crystals.

[0354] mp 98-100° C.

[0355]¹H-NMR (DMSO-d₆) δ: 2.60 (1H, dd, J=7.6 Hz, 14.8 Hz), 2.80 (1H,dd, J=5.0 Hz, 14.8 Hz), 3.28 (1H, dd, J=5.6 Hz, 10.2 Hz), 3.35 (1H, dd,J=5.4 Hz, 10.2 Hz), 3.72-3.85 (1H, m), 6.88 (2H, s).

[0356] IR (KBr): 3167, 3094, 2928, 2656, 1559, 1456, 1416, 1379, 1327,1291, 1275, 1242, 1202, 1152, 1111, 1092, 1044 cm⁻¹.

REFERENCE EXAMPLE 7

[0357] (2R)-3-(1H-imidazol-2-yl)-1,2-propanediol

[0358] (i) (2R)-1-(benzyloxy)-3-(1-trityl-1H-imidazol-2-yl)-2-propanol

[0359] In an argon atmosphere, n-butyllithium (1.6 M solution in hexane,6.9 ml) was added drop by drop to a solution of 1-tritylimidazole (3.10g) in THF (80 ml) under ice cooling. After stirring at the sametemperature for 30 minutes, (R)-2-[(benzyloxy)methyl]oxirane (1.52 ml)was added. After stirring under ice cooling for 1.5 hours and at roomtemperature for 1 hour, water was added and the reaction mixture wasextracted with ethyl acetate. The extract was washed with water andsaline and dried over magnesium sulfate, after which it was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (eluent: ethyl acetate-hexane=1:1) to yield the titledcompound (1.402 g) as a pale-yellow oily substance.

[0360]¹H-NMR (CDCl₃) δ: 2.06 (2H, dd, J=2.8 Hz, 18.0 Hz), 3.08 (1H, dd,J=5.4 Hz, 9.8 Hz), 3.21 (1H, dd, J=5.4 Hz, 9.8 Hz), 3.55-3.7 (1H, m),4.36 (2H, s), 6.73 (1H, d, J=1.4 Hz), 6.93 (1H, d, J=1.4 Hz), 7.0-7.4(20H, m).

[0361] (ii) (2R)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol

[0362] To a solution of(2R)-1-(benzyloxy)-3-(1-trityl-1H-imidazol-2-yl)-2-propanol (1.40 g) inacetone (8 ml), 1 N hydrochloric acid (8 ml) was added, followed bystirring at 50° C. for 1 hour. Additionally, 1 N hydrochloric acid (8ml) was added, followed by stirring at 50° C. for 2 hours. Afterconcentration and addition of water, the reaction mixture was twicewashed with diethyl ether. After neutralization with aqueous sodiumbicarbonate, the water layer was extracted with ethyl acetate and washedwith saline, after which it was dried over magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluent:ethyl acetate-methanol=10:1) to yieldthe titled compound (424 mg) as a colorless oily substance.

[0363]¹H-NMR (CDCl₃) δ: 2.85 (1H, dd, J=7.8 Hz, 15.6 Hz), 2.99 (1H, dd,J 3.6 Hz, 15.6 Hz), 3.39 (1H, dd, J=7.0 Hz, 9.5 Hz), 3.52 (1H, dd, J=4.4Hz, 9.5 Hz), 4.1-4.3 (1H, m), 4.55 (2H, s), 6.94 (2H, s), 7.3-7.45 (5H,m).

[0364] (iii) (2R)-3-(1H-imidazol-2-yl)-1,2-propanediol

[0365] To a solution of(2R)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (424 mg) in methanol(10 ml), 10% palladium carbon (50% hydrated, 85 mg) was added, followedby stirring at 50-60° C. in a hydrogen atmosphere for 2 days. Thecatalyst was filtered off; the filtrate was concentrated to yield thetitled compound (254 mg) as a white solid.

[0366]¹H-NMR (CDCl₃) δ: 2.58 (1H, dd, J=7.6 Hz, 14.6 Hz), 2.78 (1H, dd,J=5.2 Hz, 14.6 Hz), 3.17 (1H, d, J=5.2 Hz), 3.2-3.3 (1H, m), 3.7-3.85(1H, m), 4.6-4.7 (1H, m), 4.86 (1H, d, J=4.8 Hz), 6.76 (1H, brs), 6.95(1H, brs).

[0367] [α]_(D) ²²=+2.5° (C=1.0, methanol)

REFERENCE EXAMPLE 8

[0368] (2S)-3-(1H-imidazol-2-yl)-1,2-propanediol

[0369] (i) (3S)-4-(benzyloxy)-3-(trimethylsilyloxy)butyronitrile

[0370] To a mixture of (2S)-2-[(benzyloxy)methyl]oxirane (6.57 g) andtrimethylsilanecarbonitrile (5.0 g), potassium cyanide (26 mg) and18-crown-6 (106 mg) were added, followed by refluxing at 135° C. in anargon atmosphere for 75 minutes. After cooling, the reaction mixture wassubjected to distillation under reduced pressure to yield the titledcompound (7.42 g).

[0371]¹H-NMR (CDCl₃) δ: 0.15 (9H, s), 2.52 (1H, dd, J=6.6 Hz, 16.6 Hz),2.65 (1H, dd, J=4.6 Hz, 16.6 Hz), 3.39 (1H, dd, J=6.8 Hz, 9.6 Hz), 3.50(1H, dd, J=4.8 Hz, 9.6 Hz), 4.01-4.14 (1H, m), 4.52 (2H, s), 7.26-7.44(5H, m).

[0372] IR (neat): 3065, 3032, 2957, 2903, 2865, 2251, 1607, 1588, 1497,1454, 1416, 1366, 1254, 1209, 1117, 1001 cm⁻¹.

[0373] (ii) (3S)-4-(benzyloxy)-3-hydroxybutyronitrile

[0374] (3S)-4-(benzyloxy)-3-[(trimethylsilyl)oxy]tyronitrile (7.41 g)was dissolved in tetrahydrofuran (28.2 ml); under ice cooling andstirring, a 1 M solution of tetrabutylammonium fluoride in THF (28.2 ml)was added, followed by stirring for 1.5 hours. Under reduced pressure,the solvent was distilled off, the residue was dissolved in ether andwashed with water and saturated saline. Under reduced pressure, thesolvent was distilled off; the residue was purified by silica gel columnchromatography to yield the titled compound (4.58 g) as a colorless oilysubstance.

[0375]¹H-NMR (DMSO-d₆) δ: 2.56 (1H, dd, J=6.4 Hz, 16.8 Hz), 2.70 (1H,dd, J=4.6 Hz, 16.8 Hz), 3.34 (1H, dd, J=6.2 Hz, 9.8 Hz), 3.44 (1H, dd,J=5.4 Hz, 9.8 Hz), 3.85-3.95 (1H, m), 5.52 (2H, d, J=5.2 Hz), 7.25-7.40(5H, m).

[0376] IR (neat): 3600−3200, 3065, 3032, 2867, 2253, 1605, 1586, 1497,1454, 1416, 1364, 1308, 1254, 1208, 1101, 1078 cm⁻¹.

[0377] (iii) (2S)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol

[0378] Using (3S)-4-(benzyloxy)-3-hydroxybutyronitrile (6.51 g), a 5.12N solution of hydrogen chloride in ether (7.0 ml), and aminoacetaldehydedimethyl acetal (3.58 g), the same reaction as Reference Example 6 wascarried out to yield the titled compound (2.22 g) as a light-brown oilysubstance.

[0379]¹H-NMR (CDCl₃) δ: 2.84 (1H, dd, J=7.8 Hz, 15.4 Hz), 2.97 (1H, dd,J=3.6 Hz, 15.4 Hz), 3.41 (1H, dd, J=6.8 Hz, 9.4 Hz), 3.51 (1H, dd, J=4.4Hz, 9.4 Hz), 4.11-4.23 (1H, m), 4.54 (2H, s), 6.91 (2H, s), 7.27 (5H,m).

[0380] IR (neat): 3400−3140, 3065, 3032, 2903, 2865, 1601, 1557, 1495,1454, 1427, 1366, 1312, 1206, 1101, 1028 cm⁻¹.

[0381] [α]D²²=−2.3° (C=1.04, methanol)

[0382] (iv) (2S)-3-(1H-imidazol-2-yl)-1,2-propanediol

[0383] (2S)-1-(benzyloxy)-3-(1H-imidazol-2-yl)-2-propanol (1.725 g) wasdissolved in ethanol (30 ml); 10% palladium carbon (1.04 g) was added,followed by vigorous stirring in a hydrogen atmosphere at 60° C. and 5atm for 24 hours. The catalyst was filtered off and the solvent wasdistilled off; the residue was purified by silica gel flush columnchromatography to yield the titled compound (0.945 g).

[0384] The spectral data (¹H-NMR, IR) of this product agreed with thoseof the compound of Reference Example 6.

REFERENCE EXAMPLE 9

[0385]

[0386] (i) 4-(4-benzyloxyphenyl)-3-buten-1-ol

[0387] In an argon atmosphere, 3-hydroxypropyltriphenylphosphoniumbromide (4.02 g) was suspended in dehydrated THF (30 ml); 60% oilysodium hydride (0.4 g) was added, followed by refluxing for 3 hours. Tothe reaction mixture, a solution of 4-benzyloxybenzaldehyde (2.12 g) indehydrated THF (7 ml) was added drop by drop, followed by refluxing for67 hours. After cooling, the insoluble matter was filtered off; thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (eluent: hexane-ethyl acetate=9:1→4:1)to yield the titled compound (1.76 g) as colorless crystals.

[0388]¹H-NMR (CDCl₃) δ: 2.46 (0.8H, dq, J=1.4 Hz, 6.2 Hz), 2.61 (1.2H,dq, J=1.6 Hz, 6.4 Hz), 3.71-3.78 (2H, m), 5.06 (1.2H, s), 5.07 (1.8H,s), 5.59 (0.6H, dt, J=7.2 Hz, 11.6 Hz), 6.07 (0.4H, dt, J=7.2 Hz, 15.8Hz), 6.45 (0.4H, d, J=15.8 Hz), 6.52 (0.6H, d, J=11.6 Hz), 6.89-6.98(2H, m), 7.22-7.46 (7H, m).

[0389] IR (KBr): 3279, 3063, 3036, 3011, 2911, 2867, 1607, 1574, 1510,1470, 1454, 1383, 1302, 1250, 1177, 1117, 1053, 1017 cm⁻¹.

[0390] (ii) 4-(4-hydroxybutyl)phenol

[0391] 4-(4-benzyloxyphenyl)-3-buten-1-ol (1.70 g) was dissolved in amixture of methanol-THF (1:1, 20 ml); 10% palladium carbon (0.17 g) wasadded, followed by vigorous stirring in a hydrogen atmosphere for 1.5hours. The catalyst was filtered off; the filtrate was concentratedunder reduced pressure to yield the titled compound (1.1 g) as acolorless crystalline powder.

[0392]¹H-NMR (CDCl₃) δ: 1.50-1.76 (4H, m), 2.57 (2H, t, J=7.1 Hz), 3.67(2H, t, J=6.2 Hz), 6.74 (2H, d, J=8.4 Hz), 7.03 (2H, d, J=8.4 Hz).

[0393] IR (KBr).: 3500−3100, 3025, 2940, 2859, 1615, 1597, 1514, 1456,1362, 1240, 1173, 1107, 1055, 1024 cm⁻¹.

[0394] (iii) 4-[4-(benzyloxy)phenyl]-1-butanol

[0395] In an argon atmosphere, dry DMF (115 ml) was added to4-(4-hydroxybutyl)phenol (9.43 g) and 65% oily sodium hydride (2.4 g),followed by stirring for 15 minutes. Next, under ice cooling andstirring, a solution of benzyl bromide (9.87 g) in dry dimethylformamide(29.5 ml) was added drop by drop, followed by stirring at the sametemperature for 2 hours. After ice water and a 1 N solution of potassiumhydrogen sulfate were added, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated saline, afterwhich it was dried with anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure; the residue was purified by silicagel column chromatography to yield the titled compound (10.67 g) as acolorless crystalline powder.

[0396]¹H-NMR (DMSO-d₆) δ: 1.34-1.64 (4H, m), 2.50 (2H, t, J=7.0 Hz),3.39 (2H, dt, J=5.2 Hz, 6.4 Hz), 4.34 (1H, t, J=5.2 Hz), 5.05 (2H, s),6.90 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=8.6 Hz), 7.28-7.47 (5H, m).

[0397] IR (KBr): 3500−3200, 3048, 3036, 2928, 2907, 2861, 2840, 1615,1582, 1514, 1472, 1454, 1379, 1360, 1298, 1285, 1250, 1175, 1119, 1063,1012 cm⁻¹.

[0398] (iv) 4-[4-(benzyloxy)phenyl]butyl methanesulfonate

[0399] To a solution of 4-(4-benzyloxyphenyl)butanol (10 g) in ethylacetate (390 ml), triethylamine (8.16 ml) and methanesulfonyl chloride(4.53 ml) were added drop by drop under ice cooling. After stirring atthe ice cooling temperature for 30 minutes and at room temperature for 1hour, the reaction mixture was washed with ice water and saturatedsaline. After drying with anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure to yield the titled compound (14 g)as an oily substance. This product was used for the next process withoutpurification.

[0400]¹H-NMR (CDCl₃) δ: 1.64-1.86 (4H, m) , 2.60 (2H, t, J=7.1 Hz), 2.98(3H, s), 4.23 (2H, t, J=6.1 Hz), 5.05 (2H, s), 6.91 (2H, d, J=8.8 Hz),7.09 (2H, d, J=8.8 Hz), 7.32-7.48 (5H, m).

[0401] IR (neat): 3063, 3031, 2940, 2865, 1611, 1584, 1512, 1456, 1354,1337, 1240, 1175, 1115, 1015 cm⁻¹.

[0402] (v) Benzyl 4-(4-iodobutyl)phenyl ether

[0403] Sodium iodide (29.25 g) was dissolved in acetone (195 ml);4-[4-(benzyloxy)phenyl]butyl methanesulfonate (13 g) was added, followedby refluxing at 80° C. for 1.5 hours. After cooling, the solvent wasdistilled off; to the residue, ethyl acetate (750 ml) was added; themixture was washed sequentially with water, an aqueous solution ofsodium thiosulfate, and saturated saline. The organic layer was driedover anhydrous magnesium sulfate; the solvent was distilled off underreduced pressure to yield the titled compound (14.29 g) as an oilysubstance. This product was used for the next process withoutpurification.

[0404] 1H-NMR (CDCl₃) δ: 1.63-1.93 (4H, m) , 2.57 (2H, t, J=7.3 Hz),3.19 (2H, t, J=6.8 Hz), 5.04 (2H, s), 6.90 (2H, d, J=8.8 Hz), 7.09 (2H,d, J=8.8 Hz), 7.30-7.47 (5H, m).

[0405] IR (neat): 3063, 3031, 2932, 2857, 1611, 1582, 1510, 1454, 1381,1298, 1238, 1175, 1121, 1026 cm⁻¹.

[0406] (vi) 1-[4-(4-benzyloxyphenyl)butyl]-1H-1,2,3-triazole

[0407] Benzyl 4-(4-iodobutyl)phenyl ether (1.1 g), 1H-1,2,3-triazole(0.31 g), and potassium carbonate (0.622 g) were suspended in DMF (7.5ml), followed by stirring at 70° C. for 26.5 hours. After cooling, thereaction mixture was extracted with ethyl acetate and washed with waterand saturated saline. Under reduced pressure, the solvent was distilledoff; the residue was subjected to silica gel column chromatography(eluent:hexane-ethyl acetate=4:1→2:3) to yield the titled compound(0.391 g).

[0408]¹H-NMR (CDCl₃) δ: 1.61 (2H, quintet, J=7.8 Hz), 1.93 (2H, quintet,J=7.8 Hz), 2.59 (2H, t, J=7.6 Hz), 4.39 (2H, t, J=7.1 Hz), 5.04 (2H, s),6.90 (2H, d, J=8.8 Hz), 7.06 (2H, d, J=8.8 Hz), 7.30-7.48 (5H, m) , 7.49(1H, s) , 7.69 (1H, s).

[0409] IR (KBr): 3106, 3034, 2940, 2861, 1611, 1582, 1512, 1454, 1387,1298, 1244, 1177, 1113, 1080, 1040, 1028 cm⁻¹.

[0410] (vii) 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol

[0411] 1-[4-(4-benzyloxyphenyl)butyl)-1H-1,2,3-triazole (0.38 g) wasdissolved in methanol (7.6 ml); 10% palladium carbon (0.1 g) was added,followed by vigorous stirring in a hydrogen atmosphere for 14 hours. Thecatalyst was filtered off; the filtrate was concentrated to drynessunder reduced pressure to yield the titled compound (0.268 g) as acrystalline powder.

[0412]¹H-NMR (CDCl₃) δ: 1.60 (2H, quintet, J=7.0 Hz), 1.93 (2H, quintet,J=7.4 Hz), 2.57 (2H, t, J=7.5 Hz), 4.40 (2H, t, J=7.0 Hz), 6.79 (2H, d,J=8.6 Hz), 6.99 (2H, d, J=8.6 Hz), 7.51 (1H, s), 7.71 (1H, s).

[0413] IR (KBr): 3148, 3129, 3017, 2946, 2861, 2814, 1615, 1593, 1514,1462, 1381, 1269, 1242, 1225, 1123, 1078 cm⁻¹.

REFERENCE EXAMPLE 10

[0414] 4-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol

[0415] Benzyl 4-(3-iodopropyl)phenyl ether (2.47 g), 1H-1,2,3-triazole(629 mg), and potassium carbonate (1.26 g) were suspended in DMF (17.5ml), followed by stirring at 70° C. for 18.5 hours. The reaction mixturewas returned to room temperature and extracted with ethyl acetate, afterwhich it was washed with water and saturated saline. Under reducedpressure, the solvent was distilled off; the residue was purified bysilica gel column chromatography (eluent:hexane-ethyl acetate=4:1→2:3)to yield 1-[3-(4-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (856 mg).

[0416]¹H-NMR (CDCl₃) δ: 2.23 (2H, quintet, J=7.2 Hz), 2.60 (2H, t, J=7.5Hz), 4.38 (2H, t, J=7.1 Hz), 5.05 (2H, s), 6.92 (2H, d, J=8.8 Hz), 7.10(2H, d, J=8.8 Hz), 7.30-7.48 (5H, m), 7.52 (1H, s), 7.72 (1H, s).

[0417] IR (KBr): 3100, 3030, 2960, 2926, 2860, 1613, 1585, 1514, 1454,1383, 1298, 1250, 1215, 1177, 1115, 1082, 1044, 1028, 1019 cm⁻¹.

[0418] 1-[3-(4-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (850 mg) wasdissolved in methanol (29 ml);. 10% palladium carbon (0.1 g) was added,followed by vigorous stirring in a hydrogen atmosphere for 13 hours. Thecatalyst was filtered off; the filtrate was concentrated to drynessunder reduced pressure to yield the titled compound (600 mg) as acrystalline powder.

[0419]¹H-NMR (CDCl₃) δ: 2.22 (2H, quintet, J=7.0 Hz), 2.56 (2H, t, J=7.0Hz), 4.38 (2H, t, J=7.0 Hz), 6.87 (2H, d, J=8.6 Hz), 7.04 (2H, d, J=8.6Hz), 7.55 (1H, s), 7.74 (1H, s).

[0420] IR (KBr): 3127, 3100, 3015, 2932, 1615, 1595, 1516, 1456, 1373,1244, 1223, 1175, 1121, 1080, 1038 cm⁻¹.

REFERENCE EXAMPLE 11

[0421] 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol

[0422] (i) 3-[3-(benzyloxy)phenyl]-1-propanol

[0423] In an argon stream, 3-benzyloxybenzaldehyde (21.3 g) anddiethylphosphonoethyl acetate (23.6 g) were suspended in dry DMF (250ml). Under ice cooling and stirring, 65% oily sodium hydride (3.88 g)was added little by little; after completion of this addition, themixture was stirred at room temperature for 2 hours. After the solventwas distilled off, the residue was dissolved in ethyl acetate and washedwith water and saturated saline, after which it was dried over anhydroussodium sulfate. Under reduced pressure, the solvent was distilled off toyield 33.15 g of a crude product of ethyl(E)-3-[3-(benzyloxy)phenyl]-2-propenate as an oily substance. Thisproduct was dissolved in ethanol (406 ml); ethylenediamine-treated 5%palladium carbon [Pd-C (en), 2.7 g] was added, followed by vigorousstirring in a hydrogen atmosphere. Hydrogen (1.75 L) was consumed tocomplete hydrogenation, and the catalyst was filtered off. Under reducedpressure, the solvent was distilled off; the residue was dissolved indehydrated THF (120 ml). This solution was added drop by drop to amixture of lithium aluminum hydride (4.61 g) suspended in dehydrated THF(120 ml) under ice cooling. The reaction mixture was stirred under icecooling for 1.5 hours and at room temperature for 1 hour. The reactionmixture was added to ice water and acidified, after which it wasextracted with ethyl acetate, washed with water and saturated saline,after which it was dried over anhydrous sodium sulfate. Under reducedpressure, the solvent was distilled off; the residue was purified bysilica gel column chromatography to yield the titled compound (14.39 g)as a colorless oily substance.

[0424]¹H-NMR (CDCl₃) δ: 1.80-1.96 (2H, m), 2.69 (2H, t, J=7.7 Hz), 3.66(2H, t, J=6.4 Hz), 5.05 (2H, s), 6.77-6.87 (3H, m), 7.20 (1H, t, J=8.0Hz), 7.28-7.48 (5H, m).

[0425] IR (neat): 3330, 3063, 3032, 2940, 2867, 1599, 1582, 1487, 1453,1381, 1314, 1258, 1155, 1026 cm⁻¹.

[0426] (ii) 3-[3-(benzyloxy)phenyl]propyl methanesulfonate

[0427] Using 3-(3-benzyloxyphenyl)propanol (13.5 g), triethylamine (8.16ml) and methanesulfonyl chloride(4.53 ml), the same reaction asReference Example 9-(iv) was carried out to yield the titled compound(19.7 g) as an oily substance.

[0428]¹H-NMR (CDCl₃) δ: 2.00-2.15 (2H, m), 2.73 (2H, t, J=7.5 Hz), 2.98(3H, S), 4.22 (2H, t, J=6.3 Hz), 5.06 (2H, s), 6.77-6.88 (3H, m), 7.22(1H, t, J=7.7 Hz), 7.31-7.48 (5H, m).

[0429] IR (neat): 3032, 2940, 2870, 1599, 1584, 1487, 1453, 1381, 1354,1260, 1175, 1026 cm⁻¹.

[0430] (iii) Benzyl 3-(3-iodopropyl)phenyl ether

[0431] Using 3-[3-(benzyloxy)phenyl]propyl methanesulfonate (19.7 g) andsodium iodide (29.25 g), the same reaction as Reference Example 9-(v)was carried out to yield the titled compound (18.4 g) as an oilysubstance.

[0432]¹H-NMR (CDCl₃) δ: 2.11 (2H, quintet, J=7.3 Hz), 2.70 (2H, t, J=7.2Hz), 3.16 (2H, t, J=6.8 Hz), 5.06 (2H, s), 6.78-6.87 (3H, m), 7.21 (1H,t, J=7.2 Hz), 7.32-7.48 (5H, m).

[0433] IR (neat): 3063, 3031, 2934, 2861, 1599, 1582, 1487, 1451, 1381,1316, 1258, 1213, 1155, 1080, 1028 cm⁻¹.

[0434] (iv) 1-[3-(3-benzyloxyphenyl)propyl]-1H-1,2,3-triazole

[0435] In an argon atmosphere, 1H-1,2,3-triazole (0.9 g) was dissolvedin DMF (20 ml); 65% oily sodium hydride (0.48 g) was added. Afterstirring for 30 minutes, a solution of benzyl 3-(3-iodopropyl)phenylether (3.53 g) in DMF (5 ml) was added, followed by stirring at roomtemperature for 19 hours. The reaction mixture was diluted with ethylacetate and washed with water and saturated saline. Under reducedpressure, the solvent was distilled off; the residue was subjected tocolumn chromatography to yield the titled compound (1.1 g) as colorlesscrystals.

[0436] mp 74-75° C.

[0437]¹H-NMR (CDCl₃) δ: 2.25 (2H, quintet, J=7.2 Hz), 2.63 (2H, t, J=7.3Hz), 4.37 (2H, t, J=7.1 Hz), 5.05 (2H, s), 6.75-6.88 (3H, m), 7.23 (1H,t, J=8.2 Hz), 7.31-7.47 (5H, m), 7.49 (1H, d, J=1.0 Hz), 7.71 (1H, d,J=1.0 Hz).

[0438] IR (KBr): 3125, 3063, 3032, 2944, 2867, 1599, 1584, 1487, 1453,1381, 1316, 1260, 1215, 1157, 1113, 1074, 1028 cm⁻¹.

[0439] (v) 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol

[0440] To a solution of1-[3-(3-benzyloxyphenyl)propyl]-1H-1,2,3-triazole (0.937 g) in methanol(32 ml), 10% palladium carbon (0.1 g) was added, followed by vigorousstirring in a hydrogen atmosphere at room temperature for 8 hours. Thecatalyst was filtered off; the filtrate was concentrated to drynessunder reduced pressure to yield the titled compound (0.593 g) ascolorless crystals.

[0441] mp 85-86° C.

[0442]¹H-NMR (CDCl₃) δ: 2.24 (2H, quintet, J=7.1 Hz), 2.60 (2H, t, J=7.5Hz), 4.38 (2H, t, J=7.1 Hz), 6.68-6.79 (3H, m), 6.96 (1H, s), 7.16 (1H,t, J=8.1 Hz), 7.54 (1H, d, J=1.0 Hz), 7.73 (1H, d, J=1.0 Hz).

[0443] IR (KBr): 3129, 3077, 3054, 2949, 2863, 2722, 2614, 1599, 1588,1483, 1458, 1362, 1337, 1281, 1221, 1157, 1121, 1080, 1038 cm⁻¹.

REFERENCE EXAMPLE 12

[0444] 4-{4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl}phenol

[0445] (i)2-(1-{4-[4-(benzyloxy)phenyl]butyl}-1H-imidazol-2-yl)-1-ethanol

[0446] Benzyl 4-(4-iodobutyl)phenyl ether (14.29 g),2-(2-hydroxyethyl)imidazole (13.1 g), and potassium carbonate (5.39 g)were stirred in DMF (390 ml) at 60° C. for 16 hours. After cooling, theinsoluble matter was filtered off; the filtrate was concentrated underreduced pressure. The residue was dissolved in ethyl acetate and washedwith water and saturated saline. Under reduced pressure, the solvent wasdistilled off; the residue was purified by column chromatography(eluent: ethyl acetate-methanol=19:1→9:1). The eluate was recrystallizedfrom ethyl acetate-methanol to yield the titled compound (10.99 g) ascolorless crystals.

[0447] mp 75-77° C.

[0448]¹H-NMR (CDCl₃) δ: 1.53-1.82 (4H, m), 2.58 (2H, t, J=7.1 Hz), 2.78(2H, t, J=5.5 Hz), 3.81 (2H, t, J=6.9 Hz), 4.03 (2H, t, J=5.5 Hz), 5.04(2H, s), 6.80 (1H, d, J=1.2 Hz), 6.90 (2H, d, J=8.6 Hz), 6.93 (1H, d,J=1.2 Hz), 7.05 (2H, d, J=8.6 Hz), 7.34-7.47 (5H, m).

[0449] IR (KBr): 3144, 3032, 2934, 2859, 1611, 1582, 1514, 1495, 1456,1431, 1381, 1298, 1273, 1244, 1175, 1150, 1121, 1109, 1051, 1026 cm⁻¹.

[0450] (ii) 4-{4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl}phenol

[0451] Using2-(1-{4-[4-(benzyloxy)phenyl]butyl}-1H-imidazol-2-yl)-1-ethanol (10.67g) and 10% palladium carbon (1.6 g), the same reaction as ReferenceExample 11-(v) was carried out to yield the titled compound (5.3 g).

[0452] mp 118-119° C.

[0453]¹H-NMR (CDCl₃) δ: 1.50-1.80 (4H, m), 2.55 (2H, t, J=7.0 Hz), 2.79(2H, t, J=5.8 Hz), 3.82 (2H, t, J=7.0 Hz), 3.97 (2H, t, J=5.8 Hz),3.85-4.40 (1H, br), 6.77 (2H, d, J=8.4 Hz), 6.80 (1H, s), 6.94 (1H, s),6.96 (2H, d, J=8.4 Hz).

[0454] IR (KBr): 3600−2400, 1615, 1593, 1516, 1489, 1456, 1373, 1252,1171, 1150, 1125, 1103, 1055 cm⁻¹.

REFERENCE EXAMPLE 13

[0455]

[0456] (i)2-(1-{3-[4-(benzyloxy)phenyl]propyl)-1H-imidazol-2-yl)-1-ethanol

[0457] Using benzyl 4-(3-iodopropyl)phenyl ether (5.28 g),2-(2-hydroxyethyl)imidazole (5.05 g) and potassium carbonate (2.07 g),the same reaction as Reference Example 12-(i) was carried out to yieldthe titled compound (2.78 g) as colorless crystals.

[0458] mp 80-82° C.

[0459]¹H-NMR (CDCl₃) δ: 2.03 (2H, quintet, J=7.4 Hz), 2.58 (2H, t, J=7.4Hz), 2.74 (2H, t, J=5.6 Hz), 3.82 (2H, t, J=7.4 Hz), 4.01 (2H, t, J=5.6Hz), 5.05 (2H, s), 6.83 (1H, s), 6.92 (2H, d, J=8.6 Hz), 6.94 (1H, s),7.07 (2H, d, J=8.6 Hz), 7.32-7.47 (5H, m).

[0460] IR (KBr): 3500−3100, 3110, 3063, 3032, 2934, 2865, 1611, 1584,1512, 1495, 1454, 1381, 1298, 1240, 1177, 1152, 1121, 1057, 1024 cm⁻¹.

[0461] (ii) 4-{3-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]propyl}phenol

[0462] Using2-(1-{3-[4-(benzyloxy)phenyl]propyl}-1H-imidazol-2-yl)-1-ethanol (2.53g) and 10% palladium carbon (0.38 g), the same reaction as ReferenceExample 11-(v) was carried out to yield the titled compound (1.85 g) ascolorless crystals.

[0463] mp 116-117° C.

[0464]¹H-NMR (CDCl₃+CD₃OD) δ: 2.03 (2H, quintet, J=7.3 Hz), 2.55 (2H, t,J=7.3 Hz), 2.75 (2H, t, J=6.2 Hz), 3.83 (2H, t, J=7.3 Hz), 3.91 (2H, t,J=6.2 Hz), 6.77 (2H, d, J=8.6 Hz), 6.84 (1H, d, J=1.2 Hz), 6.93 (1H, d,J=1.2 Hz), 6.97 (2H, d, J=8.6 Hz).

[0465] IR (KBr): 3500-3100, 3119, 2934, 2861, 1615, 1593, 1516, 1495,1454, 1373, 1252, 1173, 1152, 1123, 1053 cm⁻¹.

REFERENCE EXAMPLE 14

[0466] 3-{3-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]propyl}phenol

[0467] (i)2-(1-{3-[3-(benzyloxy)phenyl]propyl}-1H-imidazol-2-yl)-1-ethanol

[0468] Using benzyl 3-(3-iodopropyl)phenyl ether (3.53 g),2-(2-hydroxyethyl)imidazole (1.46 g) and 65% oily sodium hydride (0.48g), the same reaction as Reference Example 11-(iv) was carried out toyield the titled compound (2.66 g) as a colorless oily substance.

[0469]¹H-NMR (CDCl₃) δ: 2.05 (2H, quintet, J=7.3 Hz), 2.61 (2H, t, J=7.5Hz), 2.73 (2H, t, J=5.5 Hz), 3.81 (2H, t, J=7.3 Hz), 4.02 (2H, t, J=5.5Hz), 5.06 (2H, s), 6.73-6.88 (3H, m), 6.82 (1H, d, J=1.2 Hz), 6.95 (1H,d, J=1.2 Hz), 7.23 (1H, t, J=8.2 Hz), 7.31-7.48 (5H, m).

[0470] IR (neat): 3500−3100, 3067, 3034, 2938, 2867, 1599, 1584, 1524,1491, 1453, 1381, 1316, 1260, 1155, 1119, 1053, 1026 cm⁻¹.

[0471] (ii) 3-{3-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]propyl}phenol

[0472] Using2-(1-{3-[3-(benzyloxy)phenyl]propyl}-1H-imidazol-2-yl)-1-ethanol (2.42g) and 10% palladium carbon (0.24 g), the same reaction as ReferenceExample 11-(v) was carried out to yield the titled compound (1.69 g) ascolorless crystals.

[0473] mp 111-113° C.

[0474]¹H-NMR (CDCl₃) δ: 2.07 (2H, quintet, J=6.9 Hz), 2.55 (2H, t, J=7.3Hz), 2.73 (2H, t, J=5.9 Hz), 3.80 (2H, t, J=7.1 Hz), 4.00 (2H, t, J 5.9Hz), 6.55-6.76 (3H, m), 6.86 (1H, d, J=1.4 Hz), 6.96 (1H, d, J=1.4 Hz),7.15 (1H, t, J=7.8 Hz).

[0475] IR (KBr) cmrc: 3500−3100, 3046, 2940, 2865, 2712, 2604, 1599,1588, 1528, 1483, 1456, 1372, 1279, 1250, 1155, 1123, 1057.

REFERENCE EXAMPLE 15

[0476] 3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol

[0477] (i)3-{1-[4-(4-benzyloxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol

[0478] Using benzyl 4-(4-iodobutyl)phenyl ether (2.05 g),2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride(0.259 g), the same reaction as Reference Example 11-(iv) was carriedout to yield the titled compound (1.23 g) as colorless crystals.

[0479]¹H-NMR (CDCl₃) δ: 1.52-1.83 (4H, m), 2.57 (2H, t, J=7.1 Hz), 2.78(2H, d, J=5.2 Hz), 2.79 (1H, d, J=6.8 Hz), 3.62 (1H, dd, J=4.8 Hz, 11.2Hz), 3.74 (1H, dd, J=4.8 Hz, 11.2 Hz), 3.82 (2H, t, J=7.1 Hz), 4.12-4.23(1H, m), 5.04 (2H, s), 6.79 (1H, d, J=1.4 Hz), 6.90 (2H, d, J=8.6 Hz),6.91 (1H, d, J=1.4 Hz), 7.05 (2H, d, J=8.6 Hz), 7.30-7.47 (5H, m).

[0480] IR (KBr): 3500−3200, 3065, 3030, 2932, 2861, 1611, 1582, 1510,1495, 1454, 1379, 1296, 1275, 1240, 1177, 1150, 1123, 1080, 1026 cm⁻¹.

[0481] (ii)3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol

[0482] Using3-{1-[4-(4-benzyloxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol(1.22 g) and 10% palladium carbon (0.18 g), the same reaction asReference Example 11-(v) was carried out to yield the titled compound(0.918 g) as colorless crystals.

[0483]¹H-NMR (CDCl₃+CD₃OD) δ: 1.50-1.80 (4H, m), 2.55 (2H, t, J=7.0 Hz),2.75 (1H, d, J=7.2 Hz), 2.76 (1H, d, J=5.6 Hz), 3.49 (1H, dd, J=5.4 Hz,11.6 Hz), 3.62 (1H, dd, J=4.2 Hz, 11.6 Hz), 3.84 (2H, t, J=7.0 Hz),3.97-4.08 (1H, m), 6.75 (2H, d, J=8.6 Hz), 6.80 (1H, d, J=1.4 Hz), 6.89(1H, d, J=1.4 Hz), 6.97 (2H, d, J=8.6 Hz).

[0484] IR (KBr): 3500−3100, 3011, 2936, 2859, 1613, 1595, 1516, 1489,1456, 1372, 1360, 1252, 1171, 1150, 1125, 1101, 1030 cm⁻¹.

REFERENCE EXAMPLE 16

[0485]

[0486] (i)3-{1-[3-(3-benzyloxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol

[0487] Using benzyl 3-(3-iodopropyl)phenyl ether (1.98 g),2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride(0.259 g), the same reaction as Reference Example 11-(iv) was carriedout to yield the titled compound (1.31 g) as a colorless oily substance.

[0488]¹H-NMR (CDCl₃) δ: 2.05 (2H, quintet, J=7.3 Hz), 2.60 (2H, t, J=7.3Hz), 2.73 (1H, d, J=4.8 Hz), 2.74 (1H, d, J=7.2 Hz), 3.61 (1H, dd, J=4.8Hz, 11.2 Hz), 3.74 (1H, dd, J=4.8 Hz, 11.2 Hz), 3.82 (2H, t, J=7.3 Hz),4.12-4.23 (1H, m), 5.06 (2H, s), 6.73-6.88 (3H, m), 6.81 (1H, d, J=1.2Hz), 6.93 (1H, d, J=1.2 Hz), 7.23 (1H, t, J=8.4 Hz), 7.31-7.48 (5H, m).

[0489] IR (neat): 3500−3200, 3063, 3032, 2934, 2865, 1599, 1584, 1526,1489, 1454, 1381, 1316, 1260, 1155, 1123, 1082, 1028 cm⁻¹.

[0490] (ii)3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol

[0491] Using3-{1-[3-(3-benzyloxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol(1.30 g) and 10% palladium carbon (0.195 g), the same reaction asReference Example 11-(v) was carried out to yield the titled compound(0.979 g) as a colorless oily-substance.

[0492]¹H-NMR (CDCl₃+CD₃OD) δ: 2.07 (2H, quintet, J=7.4 Hz), 2.58 (2H, t,J=7.3 Hz), 2.72 (1H, d, J=6.8 Hz), 2.72 (1H, d, J=5.8 Hz), 3.50 (1H, dd,J=5.4 Hz, 11.4 Hz), 3.61 (1H, d, J=4.2 Hz, 11.4 Hz), 3.85 (2H, t, J=7.3Hz), 3.98-4.10 (1H, m), 6.60-6.74 (3H, m), 6.86 (1H, d, J=1.4 Hz), 6.92(1H, d, J=1.4 Hz), 7.14 (1H, t, J=7.8 Hz).

[0493] IR (neat): 3500−3100, 3040, 2942, 2863, 1599, 1588, 1530, 1483,1456, 1360, 1279, 1254, 1155, 1125, 1088, 1030 cm⁻¹.

REFERENCE EXAMPLE 17

[0494]2-[(E)-2-(2,4-difluorophenyl)ethenyl]-4-[[4-(4-iodobutyl)phenoxy]methyl]-1,3-oxazole

[0495] (i)4-[4-[2-(E)-[2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxyphenyl]-1-butanol

[0496] To a solution of 4-(4-hydroxyphenyl)-1-butanol (1.99 g) in DMF(20 ml), 60% oily sodium hydride (528 mg) was added under ice cooling,followed by stirring at room temperature for 30 minutes. Under icecooling, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl)ethenyl]oxazole(3.37 g) was added, followed by stirring overnight at room temperature.After water and 1 N hydrochloric acid was added, the reaction mixturewas extracted with ethyl acetate. After the extract was dried overmagnesium sulfate, it was concentrated under reduced pressure; theresidue was recrystallized from ethyl acetate-diethyl ether-hexane toyield the titled compound (3.71 g) as colorless crystals.

[0497] mp 75-76° C.

[0498]¹H-NMR (CDCl₃) δ: 1.5-1.7 (4H, m), 2.60 (2H, t, J=6.8 Hz), 3.66(2H, t, J=6.0 Hz), 5.02 (2H, s), 6.8-6.9 (1H, m), 6.89 (2H, d, J=8.4Hz), 6.98 (1H, d, J=17.0 Hz), 7.11 (2H, d, J=8.4 Hz), 7.5-7.6 (1H, m),7.59 (1H, d, J=17.0 Hz), 7.66 (1H, s).

[0499] IR (KBr): 1613, 1514, 1493, 1431, 1279, 1246, 1140, 968, 856cm⁻¹.

[0500] (ii)2-[(E)-2-(2,4-difluorophenyl)ethenyl]-4-[[4-(4-iodobutyl)phenoxy]methyl]-1,3-oxazole

[0501] To a solution of4-[4-[2-(E)-[2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxyphenyl]-1-butanol(3.47 g) in THF (50 ml), triethylamine (1.37 ml) was added; under icecooling, methanesulfonyl chloride (0.77 ml) was added, followed bystirring at room temperature for 30 minutes. After water was added, thereaction mixture was extracted with ethyl acetate; the extract waswashed with saline, after which it was dried over magnesium sulfate. Thesolvent was distilled off; to the residue, acetone (100 ml) and sodiumiodide (6.75 g) were added, followed by stirring at 40-50° C. for 2hours. The reaction mixture was concentrated; water was added; themixture was extracted with ethyl acetate. The extract was washedsequentially with aqueous sodium thiosulfate and saline and dried overmagnesium sulfate, after which it was concentrated under reducedpressure. The precipitate was collected by filtration and washed withdiethyl ether-hexane to yield the titled compound (3.55 g) as apale-yellow powder.

[0502]¹H-NMR (CDCl₃) δ: 1.6-1.9 (4H, m) 2.5-2.7 (2H, m), 3.1-3.3 (2H,m), 5.02 (2H, s), 6.8-7.2 (6H, m), 7.5-7.75 (4H, m).

[0503] IR (KBr): 1615, 1514, 1493, 1431, 1279, 1246, 1140, 966, 856cm⁻¹.

REFERENCE EXAMPLE 18

[0504]2-[(E)-2-(4-bromophenyl)ethenyl]-4-[[4-(4-iodobutyl)phenoxy]methyl]-1,3-oxazole

[0505] Using 4-(4-hydroxyphenyl)-1-butanol (4.99 g) and(E)-4-chloromethyl-2-[2-(4-bromophenyl)ethenyl]oxazole (7.43 g), thesame reaction as Reference Example 17-(i) was carried out to yield4-[4-[2-(E)-[2-(4-bromophenyl)ethenyl]-1,3-oxazol-4-yl]methoxyphenyl]-1-butanol(9.70 g). Using the compound obtained (4.28 g), the same reaction asReference Example 17-(ii) was carried out to yield the titled compound(4.47 g) as a white powder.

[0506]¹H-NMR (CDCl₃) δ: 1.65-1.95 (4H, m) , 2.58 (2H, t, J=7.2 Hz), 3.20(2H, t, J=6.8 Hz), 5.02 (2H, s), 6.92 (1H, d, J=16.4 Hz), 6.92 (2H, d,J=8.6 Hz), 7.38 (2H, d, J=8.4 Hz), 7.47 (1H, d, J=16.4 Hz), 7.52 (2H, d,J=8.4 Hz), 7.66 (1H, s).

EXAMPLE 1

[0507][1-[4-[4-[[2-[(E)-2-(4-methylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0508] To a solution of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (174mg) in DMF (4 ml), 60% oily sodium hydride (35 mg) was added under icecooling, followed by stirring at room temperature for 30 minutes. Underice cooling, (E)-4-chloromethyl-2-[2-(4-methylphenyl)ethenyl]oxazole(206 mg) was added, followed by stirring at room temperature for 2hours. After water was added to the reaction mixture, the precipitatewas collected by filtration and washed with water. The precipitate wasdissolved in a mixture of THF-ethyl acetate, and the solution was washedwith water and saline, and dried over magnesium sulfate, after which itwas concentrated under reduced pressure. The residue was recrystallizedfrom ethyl acetate-hexane to yield the titled compound (281 mg) ascolorless crystals.

[0509] mp 154-155° C.

[0510]¹H-NMR (CDCl₃) δ: 1.5-1.7 (2H, m), 1.85-2.05 (2H, m), 2.38 (3H,s), 2.60 (2H, t, J=7.5 Hz), 4.39 (2H, t, J=7.0 Hz), 5.01 (2H, s), 6.87(2H, d, J=8.6 Hz), 6.9-7.0 (1H, m), 7.19 (2H, d, J=8.6 Hz), 7.19 (2H, d,J=8.0 Hz), 7.42 (2H, d, J=8.0 Hz), 7.5-7.7 (4H, m).

[0511] IR (KBr): 1640, 1607, 1530, 1514, 1464, 1339, 1256, 1211, 1053,974, 810 cm⁻¹.

[0512] Anal. calcd for C₂₅H₂₆N₄O₂: C, 72.44; H, 6.32; N, 13.52.

[0513] Found: C, 72.36; H, 6.49; N, 13.70.

EXAMPLE 2

[0514]1-{4-[4-({2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-1,2,3-triazole

[0515] In an argon atmosphere, 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol(218 mg) and 65% oily sodium hydride (39 mg) were dissolved in DMF (5ml) added thereto. With stirring under ice cooling,4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg)was added, followed by stirring at room temperature for 3 hours. Afterwater was added, the reaction mixture was extracted with ethyl acetate.The extract was washed with water and saturated saline and dried oversodium sulfate, after which it was concentrated under reduced pressure.The residue was purified by silica gel column chromatography(eluent:chloroform-ethanol=24:1), after which it was recrystallized fromethyl acetate to yield the titled compound (368 mg) as colorlesscrystals.

[0516] mp 124-125° C.

[0517]¹H-NMR (CDCl₃) δ: 1.62 (2H, quintet, J=7.0 Hz), 1.94 (2H, quintet,J=7.5 Hz), 2.61 (2H, t, J=7.5 Hz), 4.40 (2H, t, J=7.0 Hz), 5.01 (2H, s),6.86 (1H, d, J=16.0 Hz), 6.92 (2H, d, J=8.6 Hz), 7.08 (2H, d, J=8.6 Hz),7.09 (2H, t, J=8.7 Hz), 7.46-7.57 (4H, m), 7.66 (1H, s), 7.70 (1H, d,J=1.0 Hz).

[0518] IR (KBr): 3420, 3160, 3120, 2940, 2924, 2865, 1644, 1599, 1584,1532, 1512, 1466, 1435, 1400, 1337, 1302, 1248, 1229, 1211, 1177, 1161,1113, 1076, 1049, 1030 cm⁻¹.

[0519] Anal calcd for C₂₄H₂₃N₄O₂F: C, 68.88; H, 5.55; N, 13.39.

[0520] Found: C, 68.70; H, 5.55; N, 13.49.

EXAMPLE 3

[0521]1-{3-[3-({2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]propyl}-1H-1,2,3-triazole

[0522] Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (208 mg), 65%oily sodium hydride (39 mg) and4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg),the same reaction as Example 2 was carried out to yield the titledcompound (366 mg).

[0523] mp 105-106° C.

[0524]¹H-NMR (CDCl₃) δ: 2.26 (2H, quintet, J=7.2 Hz), 2.64 (2H, t, J=7.5Hz), 4.39 (2H, t, J=7.0 Hz), 5.03 (2H, s), 6.78-6.89 (3H, m), 6.86 (1H,d, J=16.2 Hz), 7.09 (2H, t, J=8.6 Hz), 7.25 (1H, t, J=7.8 Hz), 7.51 (1H,d, J=16.2 Hz), 7.47-7.54 (3H, m), 7.68 (1H, s), 7.72 (1H, s).

[0525] IR (KBr): 3110, 3050, 2955, 2870, 1642, 1601, 1586, 1532, 1507,1489, 1460, 1453, 1337, 1310, 1273, 1240, 1213, 1177, 1159, 1113, 1097,1080, 1065 cm⁻¹.

[0526] Anal calcd for C₂₃H₂₁N₄O₂F: C, 68.30; H, 5.23; N, 13.85.

[0527] Found: C, 68.22; H, 5.04; N, 14.00.

EXAMPLE 4

[0528]1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-1,2,3-triazole

[0529] Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oilysodium hydride (28 mg) and4-(chloromethyl)-2-((E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole(212 mg), the same reaction as Example 2 was carried out to yield thetitled compound (290 mg).

[0530] mp 160-161° C.

[0531]¹H-NMR (CDCl₃) δ: 1.62 (2H, quintet, J=7.0 Hz), 1.94 (2H, quintet,J=7.6 Hz), 2.61 (2H, t, J=7.4 Hz), 4.40 (2H, t, J=7.4 Hz), 5.02 (2H, s),6.92 (2H, d, J=8.6 Hz), 7.02 (1H, d, J=16.6 Hz), 7.08 (2H, d, J=8.6 Hz),7.50 (1H, s), 7.56 (1H, d, J=16.6 Hz), 7.64 (4H, s), 7.69 (1H, s), 7.71(1H, s).

[0532] IR (KBr): 3120, 2936, 1615, 1584, 1512, 1464, 1414, 1327, 1248,1159, 1125, 1069 cm⁻¹.

[0533] Anal calcd for C₂₅H₂₃N₄O₂F₃: C, 64.10; H, 4.95; N, 11.96.

[0534] Found: C, 64.18; H, 5.12; N, 11.98.

EXAMPLE 5

[0535]1-(3-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole.

[0536] Using 4-[3-(1H-1,2,3-triazole1-yl)propyl]phenol (143 mg), 65%oily sodium hydride (28 mg) and4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole(212 mg), the same reaction as Example 2 was carried out to yield thetitled compound (232 mg).

[0537] mp 157-158° C.

[0538]¹H-NMR (CDCl₃) δ: 2.24 (2H, quintet, J=7.2-Hz), 2.61 (2H, t, J=7.3Hz), 4.39 (2H, t, J=7.2 Hz), 5.03 (2H, s), 6.94 (2H, d, J=8.4 Hz), 7.02(1H, d, J=16.4 Hz), 7.11 (2H, d, J=8.4 Hz), 7.52 (1H, s), 7.56 (1H, d,J=16.4 Hz), 7.64 (4H, s), 7.69 (1H, s), 7.72 (1H, s).

[0539] IR (KBr): 3129, 3100, 2934, 1613, 1584, 1547, 1510, 1449, 1416,1337, 1329, 1291, 1238, 1179, 1140, 1109, 1071, 1009 cm⁻¹.

[0540] Anal calcd for C₂₄H₂₁N₄O₂F₃: C, 63.43; H, 4.66; N, 12.33.

[0541] Found: C, 63.21; H, 4.73; N, 12.26.

EXAMPLE 6

[0542]1-(3-{3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole

[0543] Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (123 mg), 65%oily sodium hydride (24 mg) and4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole(183 mg), the same reaction as Example 2 was carried out to yield thetitled compound (248 mg).

[0544] mp 115-116° C.

[0545]¹H-NMR (CDCl₃) δ: 2.26 (2H, quintet, J=7.2 Hz), 2.64 (2H, t, J=7.2Hz), 4.39 (2H, t, J=7.2 Hz), 5.04 (2H, s), 6.77-6.91 (3H, m), 7.01 (1H,d, J=16.6 Hz), 7.25 (1H, t, J=8.4 Hz), 7.52 (1H, s), 7.56 (1H, d, J=16.6Hz), 7.64 (4H, s), 7.71 (2H, s).

[0546] IR (KBr): 3140, 3050, 2940, 2860, 1610, 1599, 1586, 1487, 1451,1415, 1327, 1262, 1169, 1125, 1113, 1069, 1017 cm⁻¹.

[0547] Anal calcd for C₂₄H₂₁N₄O₂F₃: C, 63.43; H, 4.66; N, 12.33.

[0548] Found: C, 63.36; H, 4.73; N, 12.26.

EXAMPLE 7

[0549]1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-1,2,3-triazole

[0550] Using 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (152 mg), 65% oilysodium hydride (28 mg) and4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188mg), the same reaction as Example 2 was carried out to yield the titledcompound (254 mg).

[0551] mp 115-117° C.

[0552]¹H-NMR (CDCl₃) δ: 1.62 (2H, quintet, J=7.2 Hz), 1.94 (2H, quintet,J=7.5 Hz), 2.60 (2H, t, J=7.5 Hz), 4.39 (2H, t, J=7.1 Hz), 5.01 (2H, s),6.81-6.98 (2H, m), 6.91 (2H, d, J=8.6 Hz), 6.98 (1H, d, J=16.2 Hz), 7.07(2H, d, J=8.6 Hz), 7.47-7.53 (1H, m), 7.50 (1H, s), 7.59 (1H, d, J=16.2Hz), 7.67 (1H, s), 7.70 (1H, s).

[0553] IR (KBr): 3133, 2932, 2863, 1644, 1615, 1590, 1532, 1514, 1493,1468, 1431, 1345, 1298, 1279, 1246, 1215, 1179, 1140, 1086, 1049, 1032cm⁻¹.

[0554] Anal calcd for C₂₄H₂₂N₄O₂F₂: C, 66.05; H, 5.08; N, 12.84.

[0555] Found: C, 66.03; H, 5.00; N, 13.03.

EXAMPLE 8

[0556]1-{3-[3-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]propyl}-1H-1,2,3-triazole

[0557] Using 3-[3-(1H-1,2,3-triazol-1-yl)propyl]phenol (143 mg), 65%oily sodium hydride (28 mg) and4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188mg), the same reaction as Example 2 was carried out to yield the titledcompound (257 mg).

[0558] mp 89-90° C.

[0559]¹H-NMR (CDCl₃) δ: 2.26 (2H, quintet, J=7.3 Hz) , 2.64 (2H, t,J=7.4 Hz), 4.39 (2H, t, J=7.1 Hz), 5.03 (2H, s), 6.77-6.98 (5H, m), 6.98(1H, d, J=16.8 Hz), 7.24 (1H, t, J=7.6 Hz), 7.47-7.60 (1H, m), 7.52 (1H,s), 7.59 (1H, d, J=16.8 Hz), 7.68 (1H, s), 7.71 (1H, s).

[0560] IR (KBr): 3127, 3071, 2934, 2868, 1644, 1615, 1599, 1534, 1495,1453, 1433, 1354, 1273, 1215, 1159, 1142, 1090, 1028 cm⁻¹.

[0561] Anal calcd for C₂₃H₂₀N₄O₂F₂: C, 65.39; H, 4.77; N, 13.26.

[0562] Found: C, 65.32; H, 4.56; N, 13.34.

EXAMPLE 9

[0563][1-[4-[4-[[2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-1,2,3-triazole

[0564] To a solution of 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (217mg) in DMF (4 ml), 65% oily sodium hydride (41 mg) was added under icecooling. After stirring at room temperature for 30 minutes,4-(chloromethyl)-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole (281mg) was added under ice cooling, followed by overnight stirring at roomtemperature. Water was added under ice cooling; the precipitate wascollected by filtration and washed with water, after which it wasdissolved in THF-ethyl acetate. The reaction mixture was washed withwater and saline and dried over magnesium sulfate, after which it wasconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-hexane to yield the titled compound (348 mg) as colorlesscrystals.

[0565]¹H-NMR (CDCl₃) δ: 1.5-1.7 (2H, m), 1.85-2.05 (2H, m), 2.60 (2H, t,J=7.4 Hz), 4.39 (2H, t, J=7.2 Hz), 5.02 (2H, s), 6.92 (2H, d, J=8.8 Hz),6.94 (1H, d, J=17.4 Hz), 6.85-7.35 (3H, m), 7.07 (2H, d, J=8.8 Hz), 7.61(1H, d, J=17.4 Hz), 7.45-7.7 (3H, m).

[0566] IR (KBr): 1620, 1586, 1514, 1464, 1244, 1024, 999, 968, 783 cm⁻¹.

[0567] Anal. calcd for C₂₄H₂₂F₂N₄O₂: C, 66.05; H, 5.08; N, 12.84.

[0568] Found: C, 65.83; H, 5.06; N, 12.93.

EXAMPLE 10

[0569]2-[1-[4-[4-[[2-[(E)-2-(4-methylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0570] Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260mg) and (E)-4-chloromethyl-2-[2-(4-methylphenyl)ethenyl]oxazole (257mg), the same reaction as Example 1 was carried out to yield the titledcompound (331 mg) as colorless crystals.

[0571] mp 108-109° C.

[0572]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.38 (3H, s), 2.58 (2H, t,J=7.0 Hz), 2.79 (2H, t, J=5.6 Hz), 3.82 (2H, t, J=6.8 Hz), 4.03 (2H, t,J=5.6 Hz), 5.01 (2H, s), 6.8-6.85 (2H, m), 6.89 (1H, d, J=16.6 Hz), 6.92(2H, d, J=8.6 Hz), 7.07 (2H, d, J=8.6 Hz), 7.19 (2H, d, J=7.8 Hz), 7.43(2H, d, J=7.8 Hz), 7.51 (1H, d, J=16.6 Hz), 7.64 (1H, s).

[0573] IR (KBr): 1510, 1240, 1055, 806 cm⁻¹.

[0574] Anal. calcd for C₂₈H₃₁N₃O₃: C, 73.50; H, 6.83; N, 9.18.

[0575] Found: C, 73.36; H, 6.66; N, 9.12.

EXAMPLE 11

[0576]2-[1-[4-[4-[[2-[(E)-2-(3-methylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0577] Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260mg) and (E)-4-chloromethyl-2-[2-(3-methylphenyl)ethenyl]oxazole (257mg), the same reaction as Example 1 was carried out to yield the titledcompound (290 mg) as colorless crystals.

[0578] mp 109-111° C.

[0579]¹H-NMR (CDCl₃) δ: 1.55-1.8 (4H, m), 2.38 (3H, s), 2.58 (2H, t,J=7.0 Hz), 2.78 (2H, t, J 5.6 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t,J=5.6 Hz), 5.01 (2H, s), 6.80 (1H, d, J=1.4 Hz), 6.92 (1H, d, J=16.6Hz), 6.92 (2H, d, J=8.8 Hz), 6.93 (1H, d, J=1.4 Hz), 7.07 (2H, d, J=8.8Hz), 7.1-7.2 (1H, m), 7.2-7.4 (3H, m), 7.51 (1H, d, J=16.6 Hz), 7.65(1H, s).

[0580] IR (KBr): 1514, 1460, 1250, 1051, 976, 828, 789 cm⁻¹.

[0581] Anal. calcd for C₂₈H₃₁N₃O₃.0.2H₂O: C, 72.92; H, 6.86; N, 9.11.

[0582] Found: C, 72.71; H, 6.74; N, 8.97.

EXAMPLE 12

[0583]2-[1-[4-[4-[[2-[(E)-2-(2-methylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0584] Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (153mg) and (E)-4-chloromethyl-2-[2-(2-methylphenyl)ethenyl]oxazole (151mg), the same reaction as Example 1 was carried out to yield the titledcompound (167 mg) as colorless crystals.

[0585] mp 91-93° C. (ethyl acetate-hexane).

[0586]¹H-NMR(CDCl₃) δ: 1.5-1.8 (4H, m), 2.46 (3H, s) , 2.59 (2H, t,J=7.0 Hz), 2.79 (2H, t, J=5.6 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t,J=5.6 Hz), 5.02 (2H, s), 6.8-6.9 (3H, m), 6.92 (2H, d, J=8.6 Hz), 7.07(2H, d, J=8.6 Hz), 7.2-7.3 (3H, m), 7.55-7.65 (1H, m), 7.66 (1H, s),7.79 (1H, d, J=16.2 Hz).

[0587] IR (KBr): 1508, 1464, 1231, 1061, 1009, 862, 752 cm⁻¹.

[0588] Anal. calcd for C₂₈H₃₁N₃O₃.0.2H₂O: C, 72.92; H, 6.86; N, 9.11.

[0589] Found: C, 72.98; H, 6.70;. N, 9.23.

EXAMPLE 13

[0590]2-[1-[4-[4-[[2-[(E)-2-(4-ethylphenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0591] To a solution of4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) in DMF(4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling.After stirring at room temperature for 30 minutes,(E)-4-chloromethyl-2-[2-(4-ethylphenyl)ethenyl]oxazole (272 mg) wasadded under ice cooling. After stirring overnight at room temperature,water was added under ice cooling. The precipitate was collected byfiltration and washed with water. The precipitate was dissolved in ethylacetate and dried (magnesium sulfate), after which it was concentratedunder reduced pressure. The residue was recrystallized from ethylacetate-hexane to yield the titled compound (297 mg) as colorlesscrystals.

[0592] mp 94-95° C.

[0593]¹H-NMR (CDCl₃) δ: 1.25 (3H, t, J=7.4 Hz) , 1.5-1.85 (4H, m), 2.59(2H, t, J=7.0 Hz), 2.67 (2H, q, J=7.4 Hz), 2.79 (2H, t, J=5.4 Hz), 3.82(2H, t, J=7.0 Hz), 4.04 (2H, t, J=5.4), 5.01 (2H, s), 6.8-7.0 (3H, m),6.92 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4 Hz), 7.2-7.3 (2H, m), 7.4-7.5(2H, m), 7.53 (1H, d, J=17.2 Hz), 7.65 (1H, s).

[0594] IR (KBr): 1508, 1462, 1231, 1181, .1061, 1007, 864, 833 cm⁻¹.

[0595] Anal. calcd for C₂₉H₃₃N₃O₃: C, 73.86; H, 7.05; N, 8.91.

[0596] Found: C, 73.73; H, 6.79; N, 8.76.

EXAMPLE 14

[0597]2-(1-{4-[4-({2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1-ethanol

[0598] Using 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (391mg), 65% oily sodium hydride (60 mg) and4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (375 mg),the same reaction as Example 2 was carried out to yield the titledcompound (583 mg).

[0599] mp 130-132° C.

[0600]¹H-NMR (CDCl₃) δ: 1.56-1.84 (4H, m), 2.10-2.90 (1H, br), 2.58 (2H,t, J=7.1 Hz), 2.78 (2H, t, J=5.5 Hz), 3.82 (2H, t, J=7.1 Hz), 4.03 (2H,t, J=5.5 Hz), 5.01 (2H, s), 6.80-6.94 (5H, m), 7.04-7.13 (4H, m),7.46-7.55 (3H, m), 7.65 (1H, s).

[0601] IR (KBr): 3150, 3113, 3048, 2936, 2861, 1642, 1599, 1582, 1532,1512, 1464, 1422, 1399, 1375, 1337, 1302, 1277, 1246, 1229, 1209, 1177,1159, 1148, 1105, 1051, 1001 cm⁻¹.

[0602] Anal calcd for C₂₇H₂₈N₃O₃F: C, 70.26; H, 6.11; N, 9.10.

[0603] Found: C, 70.15; H, 6.06; N, 9.35

EXAMPLE 15

[0604]2-[1-[4-[4-[[2-[(E)-2-(4-chlorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0605] To a solution of4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (130 mg) in DMF(4 ml), 60% oily sodium hydride (22 mg) was added under ice cooling.After stirring at room temperature for 30 minutes,(E)-4-chloromethyl-2-[2-(4-chlorophenyl)ethenyl]oxazole (140 mg) wasadded under ice cooling. After stirring at 0° C. for 1 hour, then atroom temperature overnight, water was added under ice cooling. Theprecipitate was collected by filtration, washed with water, anddissolved in a mixture of THF-ethyl acetate. This solution was driedover magnesium sulfate, after which it was concentrated under reducedpressure. The residue was recrystallized from methanol-ethylacetate-diethyl ether to yield the titled compound (168 mg) as colorlesscrystals.

[0606] mp 127-128° C.

[0607]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.58 (2H, t, J=7.0 Hz), 2.78(2H, t, J=5.4 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t, J=5.4 Hz), 5.01(2H, s), 6.8-7.0 (5H, m), 7.07 (2H, d, J=8.8 Hz), 7.35 (2H, d, J=8.4Hz), 7.46 (2H, d, J=8.4 Hz), 7.4-7.55 (1H, m), 7.66 (1H, s).

[0608] IR (KBr): 1514, 1474, 1341, 1264, 1246, 1076, 966, 814 cm⁻¹.

[0609] Anal. calcd for C₂₇H₂₈ClN₃O₃: C, 67.85; H, 5.90; N, 8.79.

[0610] Found: C, 67.85; H, 5.72; N, 9.09.

EXAMPLE 16

[0611]2-[1-[4-[4-[[2-[(E)-2-(4-bromophenyl)ethenyl]-1,3-oxazol-4-yl]methoxylphenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0612] To a solution of 2-(1H-imidazol-2-yl)-ethanol (449 mg) in DMF (10ml), 60% oily sodium hydride (176 mg) was added under ice cooling. Afterstirring at room temperature for 30 minutes,4-[[4-(4-iodobutyl)phenoxy)methyl]-2-[(E)-2-(4-bromophenyl)ethenyl]-1,3-oxazole(2.15 g) was added under ice cooling. After stirring overnight at roomtemperature, water was added under ice cooling. The reaction mixture wasextracted with a mixture of ethyl acetate-THF. The extract was driedover magnesium sulfate, after which it was concentrated under reducedpressure. The residue was recrystallized from ethyl acetate-hexane toyield the titled compound (2.09 g) as a light-yellow crystal.

[0613] mp 149-150° C.

[0614]¹H-NMR (CDCl₃) δ: 1.55-1.8 (4H, m), 2.58 (2H, t, J=7.0 Hz), 2.78(2H, t, J=5.6 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t, J=5.6 Hz), 5.01(2H, s), 6.91 (2H, d, J=8.8 Hz), 6.92 (1H, d, J=16.3 Hz), 6.8-7.0 (2H,m), 7.07 (2H, d, J=8.8 Hz), 7.38 (2H, d, J=8.6 Hz), 7.47 (1H, d, J=16.3Hz), 7.52 (2H, d, J=8.6 Hz) , 7.66 (1H, s)

[0615] IR (KBr): 1514, 1487, 1254, 1055, 972, 826, 814 cm⁻¹.

[0616] Anal. calcd for C₂₇H₂₈BrN₃O₃: C, 62.07; H, 5.40; N, 8.04.

[0617] Found: C, 61.82; H, 5.26; N, 7.90.

EXAMPLE 17

[0618]2-[1-[4-[4-[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methoxyphenyl]butyl-1H-imidazol-2-yl]-1-ethanol

[0619] In an argon atmosphere, DMF (4 ml) was added to a mixture of 65%sodium hydride (40.6 mg) and4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) at 0° C.After stirring at room temperature for 30 minutes,[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methyl chloride(316 mg) was added at 0° C., followed by stirring at room temperaturefor 15 hours, After water was added to the reaction mixture, theprecipitated crystal was collected by filtration, washed with water andisopropyl ether, after which it was recrystallized from acetone-hexaneto yield the titled compound (393 mg) as pale-yellow needles.

[0620]¹H-NMR (CDCl₃) δ: 1.56-1.74 (4H, m), 2.59 (2H, t, J=6.6 Hz), 2.78(2H, t, J=5.4 Hz), 3.82 (2H, t, J=6.8 Hz), 4.03 (2H, t, J=5.4 Hz), 5.02(2H, d, J=1.2 Hz), 6.81 (1H, d, J=1.6 Hz), 6.90-6.95 (4H, m), 7.02 (2H,d, J=16.2 Hz), 7.52-7.69 (6H, m).

[0621] IR (KBr): 1512, 1323, 1244. 1175, 1132, 1113, 1067, 1055 cm⁻¹.

EXAMPLE 18

[0622]2-[1-[3-[4-[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methoxyphenyl]propyl]-1H-imidazol-2-yl]-1-ethanol

[0623] Using 65% sodium hydride (40.6 mg),4-[3-[2-(hydroxyethyl)-1H-imidazol-1-yl]propyl]phenol (246 mg) and[2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]oxazol-4-yl]methyl chloride(316 mg), the same reaction as Example 17 was carried out to yield thetitled compound (330 mg) as colorless needles.

[0624]¹H-NMR (CDCl₃) δ: 2.01-2.08 (2H, m) , 2.60 (2H, t, J=7.8 Hz), 2.74(2H, t, J=5.8 Hz), 3.83 (2H, t, J=7.4 Hz), 4.03 (2H, t, J=5.8 Hz), 5.03(2H, s), 6.84 (1H, d, J=1.2 Hz), 6.96-7.12 (6H, m), 7.52-7.70 (6H, m).

[0625] IR (KBr): 1512, 1327, 1246, 1173, 1125, 1069, 1017, 826 cm⁻¹.

EXAMPLE 19

[0626]2-[1-[4-[4-[[2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxylphenyl]butyl]-1H-imidazol-2-yl]-1-ethanol

[0627] To a solution of4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (260 mg) in DMF(4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling.After stirring at room temperature for 30 minutes,(E)-4-chloromethyl-2-[2-(2,4-difluorophenyl)ethenyl]oxazole (281 mg) wasadded under ice cooling. After stirring at room temperature for 3 days,water was added under ice cooling. The precipitate was collected byfiltration and washed with water. The precipitate was dissolved in amixture of ethyl acetate-THF and dried over magnesium sulfate, afterwhich it was concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-hexane to yield the titled compound(275 mg) as pale-yellow crystals.

[0628] mp 93-95° C.

[0629]¹H-NMR (CDCl₃) δ: 1.55-1.85 (4H, m), 2.58 (2H, t, J=7.0 Hz), 2.78(2H, t, J=5.4 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t, J=5.4 Hz), 5.01(2H, s), 6.8-7.0 (6H, m), 6.98 (1H, d, J=16.3 Hz), 7.07 (2H, d, J=8.8Hz), 7.5-7.6 (1H, m), 7.59 (1H, d, J=16.3 Hz), 7.67 (1H, s).

[0630] IR (KBr): 1611, 1508, 1277, 1231, 1140, 1103, 1063, 970, 860cm⁻³.

[0631] Anal. calcd for C₂₇H₂₇F₂N₃O_(3.)0.1H₂O: C, 67.38; H, 5.70; N,8.73.

[0632] Found: C, 67.24; H, 5.74; N, 8.55.

EXAMPLE 20

[0633]2-[1-[3-[4-[[2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]propyl]-1H-imidazol-2-yl]-1-ethanol

[0634] To a solution of4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]propyl]phenol (246 mg) in DMF(4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling.After stirring at room temperature for 30 minutes,(E)-4-chloromethyl-2-[2-(2,4-difluorophenyl)ethenyl]oxazole (281 mg) wasadded under ice cooling. After stirring overnight at room temperature,water was added under ice cooling. The precipitate was collected byfiltration and washed with water. The precipitate was dissolved in ethylacetate and dried over magnesium sulfate, after which it wasconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate-diethyl ether-hexane to yield the titled compound (272 mg)as colorless crystals.

[0635] mp 94-96° C.

[0636]¹H-NMR (CDCl₃) δ: 1.95-2.15 (2H, m), 2.5-2.65 (2H, m), 2.65-2.8(2H, m), 3.75-3.9 (2H, m), 3.95-4.1 (2H, m), 5.02 (2H, s), 6.8-7.15 (9H,m), 7.45-7.7 (3H, m).

[0637] IR (KBr): 1609, 1512, 1277, 1231, 1140, 1061, 1020, 974, 860cm⁻¹.

[0638] Anal. calcd for C₂₆H₂₅F₂N₃O₃.0.4H₂O: C, 66.06; H, 5.50; N, 8.89.

[0639] Found: C, 66.13; H, 5.38; N, 8.55.

EXAMPLE 21

[0640]2-[1-[3-[4-[[2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]propyl]-1H-imidazol-2-yl]-1-ethanol

[0641] Using 2-(2-hydroxyethyl)-1-[4-(4-hydroxyphenyl)butyl]imidazole(260 mg), 60% oily sodium hydride (41 mg) and(E)-4-chloromethyl-2-[2-(2,6-difluorophenyl)ethenyl]oxazole (281 mg),the same reaction as Example 19 was carried out to yield the titledcompound (359 mg) as colorless crystals.

[0642] mp 106-107° C.

[0643]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.58 (2H, t, J=7.0 Hz), 2.78(2H, t, J=5.6 Hz), 3.82 (2H, t, J=7.0 Hz), 4.03 (2H, t, J=5.6 Hz), 5.02(2H, s), 6.8-7.0 (6H, m), 7.07 (2H, d, J=8.4 Hz), 7.2-7.35 (2H, m), 7.61(1H, d, J=16.8 Hz), 7.68 (1H, s).

[0644] IR (KBr): 1618, 1516, 1472, 1456, 1246, 1065, 1001, 974, 789cm⁻¹.

[0645] Anal. calcd for C₂₇H₂₇F₂N₃O₃: C, 67.63; H, 5.68; N, 8.76.

[0646] Found: C, 67.78; H, 5.57; N, 9.01.

EXAMPLE 22

[0647]3-(1-{4-[4-({2-[(E)-2-(3-methylphenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol

[0648] Using3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol (154mg), 65% oily sodium hydride (21 mg) and4-(chloromethyl)-2-[(E)-2-(3-methylphenyl)ethenyl]-1,3-oxazole (131 mg),the same reaction as Example 2 was carried out to yield the titledcompound (156 mg).

[0649] mp 102-104° C.

[0650]¹H-NMR (CDCl₃) δ: 1.52-1.82 (4H, m) , 2.39 (3H, s) 2.59 (2H, t,J=7.0 Hz), 2.77 (1H, d, J=5.0 Hz), 2.78 (1H, d, J=6.8 Hz), 3.64 (1H, dd,J=4.8 Hz, 11.2 Hz), 3.76 (1H, dd, J=4.2 Hz, 11.2 Hz), 3.82 (2H, t, J=7.0Hz), 4.12-4.24 (1H, m), 5.02 (2H, s), 6.80 (1H, d, J=1.4 Hz), 6.92 (1H,d, J=1.4 Hz), 6.93 (1H, d, J=16.2 Hz), 6.93 (1H, d, J=8.8 Hz), 7.08 (2H,d, J=8.8 Hz), 7.13-7.39 (4H, m), 7.52 (1H, d, J=16.2 Hz), 7.66 (1H, s).

[0651] IR (KBr): 3500−3200, 3112, 3029, 2934, 2865, 1645, 1609, 1584,1510, 1491, 1462, 1379, 1350, 1242, 1177, 1150, 1123, 1100, 1026 cm⁻¹.

[0652] Anal calcd for C₂₉H₃₃N₃O₄.0.5H₂O: C, 70.14; H, 6.90; N, 8.46.

[0653] Found: C, 70.39; H, 6.63; N, 8.51

EXAMPLE 23

[0654]3-(1-{4-[4-({2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol

[0655] Using3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl)-1,2-propanediol (291mg), 65% oily sodium hydride (39 mg) and4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg),the same reaction as Example 2 was carried out to yield the titledcompound (347 mg).

[0656] mp 114-116° C.

[0657]¹H-NMR (CDCl₃) δ: 1.52-1.83 (4H, m), 2.59 (2H, t, J=7.2 Hz), 2.76(1H, d, J=5.2 Hz), 2.77 (1H, d, J=7.0 Hz), 3.64 (1H, dd, J=4.8 Hz, 11.4Hz), 3.76 (1H, dd, J=4.2 Hz, 11.4 Hz), 3.82 (2H, t, J=6.8 Hz), 4.12-4.24(1H, m), 5.01 (2H, s), 6.80 (1H, d, J=1.4 Hz), 6.86 (1H, d, J=16.8 Hz),6.92 (1H, d, J=1.4 Hz), 6.93 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.8 Hz),7.09 (2H, d, J=8.7 Hz), 7.46-7.56 (3H, m), 7.66 (1H, s).

[0658] IR (KBr): 3500−3200, 3152, 3104, 3044, 2940, 2865, 1644, 1599,1584, 1532, 1512, 1495, 1462, 1422, 1400, 1339, 1300, 1246, 1177, 1159,1098, 1047 cm⁻¹.

[0659] Anal calcd for C₂₈H₃₀N₃O₄F: C, 68.42; H, 6.15; N, 8.55.

[0660] Found: C, 68.16; H, 5.98; N, 8.46

EXAMPLE 24

[0661]3-[1-(4-{4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1H-imidazol-2-yl]-1,2-propanediol

[0662] Using3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl)-1,2-propanediol (204mg), 65% oily sodium hydride (28 mg) and4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl)-1,3-oxazole(212 mg), the same reaction as Example 2 was carried out to yield thetitled compound (285 mg).

[0663] mp 142-143° C.

[0664]¹H-NMR (CDCl₃) δ: 1.53-1.82 (4H, m), 2.59 (2H, t, J=7.1 Hz), 2.76(1H, d, J=5.0 Hz), 2.77 (1H, d, J=7.0 Hz), 3.64 (1H, dd, J=4.8 Hz, 11.4Hz), 3.76 (1H, dd, J=4.2 Hz, 11.4 Hz), 3.83 (2H, t, J=6.8 Hz), 4.12-4.24(1H, m), 5.02 (2H, s), 6.81 (1H, d, J=1.4 Hz), 6.92 (1H, d, J=1.4 Hz),6.93 (2H, d, J=8.8 Hz), 6.95 (1H, d, J=16.4 Hz), 7.08 (2H, d, J=8.8 Hz),7.56 (1H, d, J=16.4 Hz), 7.64 (4H, s), 7.70 (1H, s).

[0665] IR (KBr): 3500−3200, 3148, 3071, 2936, 2867, 1642, 1615, 1582,1510, 1491, 1466, 1416, 1397, 1323, 1246, 1173, 1138, 1117, 1067, 1046,1017 cm⁻¹.

[0666] Anal calcd for C₂₉H₃₀N₃O₄F₃: C, 64.32; H, 5.58; N, 7.76.

[0667] Found: C, 64.26; H, 5.70; N, 7.62

EXAMPLE 25

[0668]3-[1-(3-(3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxylphenyl]propyl)-1H-imidazol-2-yl]-1,2-propanediol

[0669] Using3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl)-1,2-propanediol (194mg), 65% oily sodium hydride (28 mg) and4-(chloromethyl)-2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazole(212 mg), the same reaction as Example 2 was carried out to yield thetitled compound (255 mg).

[0670] mp 102-104° C.

[0671]¹H-NMR (CDCl₃) δ: 2.08 (2H, quintet, J=7.0 Hz), 2.62 (2H, t, J=7.4Hz), 2.72 (1H, d, J=4.8 Hz), 2.73 (1H, d, J=7.6 Hz), 3.63 (1H, dd, J=4.8Hz, 11.4 Hz), 3.74 (1H, dd, J=4.2 Hz, 11.4 Hz), 3.83 (2H, t, J=7.2 Hz),4.13-4.24 (1H, m), 5.03 (2H, s), 6.77-6.91 (3H, m), 6.84 (1H, d, J=1.4Hz), 6.94 (1H, d, J=1.4 Hz), 7.02 (1H, d, J=16.4 Hz), 7.25 (1H, t, J=7.8Hz), 7.57 (1H, d, J=16.4 Hz), 7.64 (4H, s), 7.71 (1H, s).

[0672] IR (KBr): 3500−3200, 3108, 3056, 2932, 2867, 1613, 1599, 1586,1534, 1489, 1451, 1416, 1325, 1260, 1167, 1125, 1069, 1030, 1017 cm⁻¹.

[0673] Anal calcd for C₂₈H₂₈N₃O₄F₃: C, 63.75; H, 5.35; N, 7.97.

[0674] Found: C, 63.60; H, 5.32; N, 7.88

EXAMPLE 26

[0675]3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol

[0676] Using3-{1-[4-(4-hydroxyphenyl)butyl]-1H-imidazol-2-yl}-1,2-propanediol(204mg), 65% oily sodium hydride (28 mg) and4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (188mg), the same reaction as Example 2 was carried out to yield the titledcompound (223 mg).

[0677] mp 126-128° C.

[0678]¹H-NMR (CDCl₃) δ: 1.52-1.81 (4H, m), 2.58 (2H, t, J=6.9 Hz), 2.77(2H, d, J=5.4 Hz), 3.63 (1H, dd, J=4.8 Hz, 11.4 Hz), 3.75 (1H, dd, J=4.2Hz, 11.4 Hz), 3.82 (2H, t, J=7.0 Hz), 4.10-4.24 (1H, m), 5.01 (2H, s),6.76-7.02 (7H, m), 7.07 (2H, d, J=8.6 Hz), 7.48-7.51 (1H, m), 7.59 (1H,d, J=16.6 Hz), 7.67 (1H, s).

[0679] IR (KBr): 3500−3200, 3106, 3073, 3032, 2934, 2865, 1644, 1613,1593, 1532, 1512, 1495, 1462, 1431, 1354, 1298, 1275, 1244, 1177, 1142,1090, 1028 cm⁻¹.

[0680] Anal calcd for C₂₈H₂₉N₃O₄F₂: C, 66.00; H, 5.74; N, 8.25.

[0681] Found: C, 65.89; H, 5.94; N, 8.37

EXAMPLE 27

[0682]3-(1-{3-[3-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]propyl}-1H-imidazol-2-yl)-1,2-propanediol

[0683] Using3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (203mg), 65% oily sodium hydride (29 mg) and4-(chloromethyl)-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole (197mg), the same reaction as Example 2 was carried out to yield the titledcompound (220 mg).

[0684] mp 92-94° C.

[0685]¹H-NMR (CDCl₃) δ: 2.08 (2H, quintet, J=7.2 Hz), 2.62 (2H, t, J=7.3Hz), 2.73 (1H, d, J=5.0 Hz), 2.74 (1H, d, J=7.0 Hz), 3.63 (1H, dd, J=4.8Hz, 11.2 Hz), 3.74 (1H, dd, J=4.2 Hz, 11.2 Hz), 3.83 (2H, t, J=7.4 Hz),4.14-4.24 (1H, m), 5.02 (2H, s), 6.76-6.98 (5H, m), 6.84 (1H, d, J=1.4Hz), 6.93 (1H, d, J=1.4 Hz), 6.98 (1H, d, J=16.4 Hz), 7.25 (1H, t, J=7.9Hz), 7.48-7.61 (1H, m), 7.60 (1H, d, J=16.4 Hz), 7.69 (1H, s).

[0686] IR (KBr): 3500−3200, 3106, 3067, 3042, 2938, 2872, 1644, 1613,1599, 1534, 1495, 1453, 1431, 1379, 1354, 1275, 1155, 1142, 1123, 1090,1028 cm⁻¹.

[0687] Anal calcd for C₂₇H₂₇N₃O₄F₂: C, 65.44; H, 5.49; N, 8.48.

[0688] Found: C, 65.39; H, 5.32; N, 8.62.

EXAMPLE 28

[0689]3-[1-[4-[4-[[2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1,2-propanediol

[0690] Using3-{1-[3-(3-hydroxyphenyl)propyl]-1H-imidazol-2-yl}-1,2-propanediol (142mg), 60% oily sodium hydride (40 mg) and4-(chloromethyl)-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole (495mg), the same reaction as Example 2 was carried out to yield the titledcompound (395 mg) as colorless crystals.

[0691] mp 123-125° C.

[0692]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.59 (2H, t, J=7.0), 2.7-2.8(2H, m), 3.6-3.75 (2H, m), 3.83 (2H, t, J=7.0 Hz), 4.1-4.25 (1H, m),5.03 (2H, s), 6.8-7.0 (4H, m), 6.92 (2H, d, J=8.6 Hz), 7.07 (2H, d,J=8.6 Hz), 7.2-7.3 (1H, m), 7.29 (1H, d, J=16.8 Hz), 7.61 (1H, d, J=16.8Hz), 7.69 (1H, s).

[0693] IR (KBr): 1620, 1508, 1458, 1236, 1051, 1001, 789 cm⁻¹.

[0694] Anal. calcd for C₂₈H₂₉F₂N₃O₄: C, 66.00; H, 5.74; N, 8.25.

[0695] Found: C, 65.71; H, 5.78; N, 8.09.

EXAMPLE 29

[0696](2R)-3-[[1-[4-[4-[[2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxylphenyl]butyl]-1H-imidazol-2-yl]-1,2-propanediol

[0697] To a solution of (2R)-3-(1H-imidazol-2-yl)-1,2-propanediol (127mg) in DMF (4 ml), 60% oily sodium hydride (37 mg) was added under icecooling. After stirring at room temperature for 30 minutes,4-[[4-(4-iodobutyl)phenoxy]methyl]-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole(485 mg) was added under ice cooling. After stirring at room temperaturefor 3 hours, water was added under ice cooling. The reaction mixture wasextracted with a mixture of THF-ethyl acetate and washed with water andsaline and dried over magnesium sulfate, after which it was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: ethyl acetate-methanol=10:1), after which it wasrecrystallized from ethyl acetate-hexane to yield the titled compound(262 mg) as colorless crystals.

[0698] mp 104-106° C.

[0699]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.59 (2H, t, J=7.0 Hz), 2.7-2.8(2H, m), 3.55-3.75 (2H, m), 3.79 (2H, t, J=7.0 Hz), 4.1-4.2 (1H, m),5.01 (2H, s), 6.8-7.1 (5H, m), 6.92 (2H, d, J=8.4 Hz), 7.07 (2H, d,J=8.4 Hz), 7.5-7.6 (1H, m), 7.59 (1H, d, J=16.2 Hz), 7.67 (1H, s).

[0700] IR (KBr): 1507, 1472, 1273, 1235, 1140, 1092, 966, 858 cm⁻¹.

[0701] Anal. calcd for C₂₈H₂₉F₂N₃O₄: C, 66.00; H, 5.74; N, 8.25.

[0702] Found: C, 65.69; H, 5.82; N, 8.06.

[0703] [α]²² _(D)=+4.2° (c=1.0, methanol).

EXAMPLE 30

[0704](2S)-3-[[1-[4-[4-[[2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1,2-propanediol

[0705] Using (2S)-3-(1H-imidazol-2-yl)-1,2-propanediol, 60% oily sodiumhydride (50 mg) and4-[[4-(4-iodobutyl)phenoxy]methyl]-2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazole(415 mg), the same reaction as Example 29 was carried out to yield thetitled compound (219 mg) as colorless crystals.

[0706] mp 106-108° C.

[0707]¹H-NMR (CDCl₃) δ: 1.5-1.8 (4H, m), 2.58 (2H, t, J=6.8 Hz), 2.7-2.8(2H, m), 3.6-3.75 (2H, m), 3.82 (2H, t, J=7.0 Hz), 4.1-4.2 (1H, m), 5.01(2H, s), 6.8-7.1 (5H, m), 6.89 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4Hz), 7.5-7.6 (1H, m), 7.59 (1H, d, J=16.4 Hz), 7.67 (1H, s).

[0708] IR (KBr): 1615, 1512, 1497, 1273, 1246, 1229, 1140, 1094, 1046,966, 847 cm⁻¹.

[0709] Anal. calcd for C₂₈H₂₉F₂N₃O₄: C, 66.00; H, 5.74; N, 8.25.

[0710] Found: C, 65.75; H, 5.60; N, 8.12.

[0711] [α]²² _(D)=−3.5° (c=1.0, methanol).

PREPARATION EXAMPLE 1 (AMOUNT PER TABLET)

[0712] (1) Compound obtained in Example 4 10.0 mg (2) Lactose 60.0 mg(3) Corn starch 35.0 mg (4) Gelatin  3.0 mg (5) Magnesium stearate  2.0mg

[0713] A mixture of 10.0 mg of the compound obtained in Example 4, 60.0mg of lactose, and 35.0 mg of corn starch was granulated through a 1mm-mesh sieve using 0.03 ml of a 10% by weight aqueous solution ofgelatin (3.0 mg of gelatin), after which the granules were dried at 40°C. and filtered again. The granules obtained were mixed with 2.0 mg ofmagnesium stearate and compressed. The core tablets obtained were coatedwith a sugar coat comprising a suspension of sucrose, titanium dioxide,talc, and gum arabic and polished with beeswax to yield sugar-coatedtablets.

PREPARATION EXAMPLE 2 (DOSE PRE TABLET)

[0714] (1) Compound obtained in Example 4 10.0 mg (2) Lactose 70.0 mg(3) Corn starch 50.0 mg (4) Soluble starch  7.0 mg (5) Magnesiumstearate  3.0 mg

[0715] 10.0 mg of the compound obtained in Example 4 and 3.0 mg ofmagnesium stearate were granulated using 0.07 ml of an aqueous solutionof solubilized starch (7.0 mg of solubilized starch), after which thesegranules were dried and mixed with 70.0 mg of lactose and 50.0 mg ofcorn starch. This mixture was compressed to yield tablets.

[0716] In the following Test Examples, Compound Numbers indicatecorresponding Example Numbers (e.g., the compound of Example 2 isindicated by Compound 2).

TEST EXAMPLE 1

[0717] Suppression of Receptor Tyrosine-Phosphorylation in Human BreastCancer Cells

[0718] Cells of human breast cancer cell line MCF-7 were suspended at300,000 cells/0.5 mL, sown were into a 24-well plate, and cultured at37° C. in the presence of 5% carbon dioxide. On the following day, 250μl of a solution of the test compound times was added. After 2 hours,250 μl of a heregulin solution, prepared to a final concentration of 0.8μg/ml, was added. After 5 minutes, the a buffer solution for cell lysiswas added to stop the reaction and yield a cell-lysed solution. Afterthis cell-lysed solution was subjected to this protein wasSDS-polyacrylamide gel electrophoresis to separate the protein, in thegel was transferred to a nylon filter. The protein in the gel wasblotted onto a nylon filter. This filter was reacted with ananti-phosphotyrosine antibody; the portion containing phosphotyrosine onthe filter was luminated using the ECL method to photosensitize an X-rayfilm. The amount of film photosensitization was determined using animage analyzer. Taking as 100% the amount of phosphorylation of the HER2tyrosine inof the heregulin group, the ratio of the amount ofphosphorylation of the HER2 tyrosine in each group receiving a solutionof the test compound at each concentration was determined, and the testcompound concentration required to achieve 50% suppression by the testcompound of the amount of phosphorylation of HER2 tyrosine (IC₅₀ value)was calculated. The results are shown in Table 1. This finding showedthat the compound of the present invention potently inhibits thephosphorylation reaction of the tyrosine residue of the receptor.protein caused by activation of the receptor tyrosine kinase due togrowth factor stimulation upon stimulation of human breast cancer cellsby the growth factor heregulin. TABLE 1 Inhibition of intracellular HER2Example number phosphorylation (compound number) MCF-7 (IC₅₀: μM) 2 1.93 0.18 4 0.10 6 1.2 11 1.1 20 1.5 22 1.9 26 0.92

TEST EXAMPLE 2 Inhibitory Action on Breast Cancer Proliferation (InVitro)

[0719] Cells of human breast cancer cell line BT-474 (1,000 cells/100μl) were sown to a 96-well microwillplate and cultured at 37° C. in thepresence of 5% carbon dioxide. On the following day, 100 μl of asolution of each test compound, previously diluted 2-fold with aheregulin solution prepared to a final concentration of 0.04 μg/ml, wasadded, and the cells were cultured for 5 days. After the culture mediumcontaining the test compound was removed, the cells were washed andfixed with 5% trichloroacetic acid, after which a 0.4% (w/v) SRBsolution (dissolved in 1% acetic acid) was added to stain the cells(Skehan et al., Journal of the National Cancer Institute, Vol. 82, pp.1107-1112, 1990). After the pigment solution was removed and the platewas washed with a 1% acetic acid solution, 100 μl of an extractant (10mM Tris solution) was added to dissolve the pigment; absorbance wasmeasured at an absorption wavelength of 550 nm to quantify the amount ofcells as protein content. Taking as 100% the absorbance for the controlgroup, which received no test compound solution, the ratio of theabsorbance for each treatment group was determined, and the compoundconcentration required to achieve 50% suppression of the residual cellcontent relative to the control (IC₅₀ value) was calculated. The resultsare shown in Table 2.

[0720] The compound of the present invention was thus shown to potentlysuppress the proliferation of cells of the human breast cancer cell lineBT-474. TABLE 2 Example number Cell growth inhibition (compound number)BT-474 (IC₅₀: μM) 2 <0.05 3 <0.05 4 <0.05 6 <0.05 11 <0.05 19 0.017 20<0.05 22 <0.05 26 <0.05

TEST EXAMPLE 3

[0721] Inhibitory Action on Breast Cancer Cell Proliferation (In Vivo)

[0722] 5,000,000 cells of human breast cancer cell line BT-474 weresuspended in Matrigel solution and transplanted subcutaneously atto afemale BALB/c nude mouse (6 weeks of age) (Freedman et al., Proceedingsof the National Academy of Science, USA, Vol. 87, pp. 6698-6702, 1990).Immediately after transplantation and at 7 days after transplantation,50 μL of estradiol dipropionate (5 mg/mL solution) was administeredintramuscularly into a hind legthe. At 14 days after transplantation,tumor diameter was measured, and 5 mice per group, uniformized withrespect to tumor size, were used for the experiment. The compound of thepresent invention (4, 6, 14, 17, 19, 20, 23, 24, 26) in a 5% gum arabicsuspension (physiological saline) was administered orally at a dose of30 mg/kg twice daily for 10 days. On the day of administrationinitiation and the day after administration completion, tumor diameterwas measured, and tumor volume was calculated using the equation shownbelow.

Tumor volume=maximum diameter×minimum diameter×minimum diameter×(½)

[0723] The ratio of the value obtained by subtracting the tumor volumeon the day of administration initiation from the tumor volume on the dayafter administration completion in the control group, which received angum arabic solution, and to that the value obtained by subtracting thetumor volume at the day of administration initiation from the tumorvolume at the day of administration completion in each drugadministration group was obtained as the proliferation rate. The resultsare shown in Table 3.

[0724] The compound of the present invention suppressed the growth ofhuman breast cancer cells transplanted to nude mice. Mice were weighedduring the test period; no body weight loss due to administration of thecompound of the present invention was observed. TABLE 3 Example No.(Compound No.) Proliferation rate (%) 4 5 6 28 23 27 24 28 26 15

[0725] Industrial Applicability

[0726] Since Compound (I) of the present invention or a salt thereofpossesses tyrosine kinase-inhibiting activity and is of low toxicity, itcan be used to prevent or treat tyrosine kinase-dependent diseases inmammals. Tyrosine kinase-dependent diseases include diseasescharacterized by increased cell proliferation due to abnormal tyrosinekinase enzyme activity. Furthermore, Compound (I) of the presentinvention or a salt thereof specifically inhibits tyrosine kinase and istherefore also useful as a therapeutic agent for suppressing the growthof HER2-expressing cancer, or a preventive gent for preventing thetransition of hormone-dependent cancer to hormone-independent cancer.

1. A compound represented by the formula:

wherein m is 1 or 2; R¹ is a halogen atom or an optionally halogenatedC₁₋₂ alkyl group; one of R² and R³ is a hydrogen atom and the other is agroup represented by the formula:

wherein n is 3 or 4; R⁴ is a C₁₋₄ alkyl group substituted by 1 or 2hydroxy groups, or a salt thereof.
 2. A compound as claimed in claim 1,wherein R¹ is fluoro or trifluoromethyl, or a salt thereof.
 3. Acompound as claimed in claim 1, wherein R² is a group represented by theformula:

and R³ is a hydrogen atom; or R² is a hydrogen atom and R³ is a grouprepresented by the formula:

or a salt thereof.
 4. A compound as claimed in claim 1, wherein R² is agroup represented by the formula:

and R³ is a hydrogen atom, or a salt thereof.
 5. A compound as claimedin claim 1, wherein m is 1; R¹ is 4-trifluoromethyl; R² is a grouprepresented by the formula:

and R³ is a hydrogen atom, or a salt thereof.
 6. A compound as claimedin claim 1, which is1-4-(4-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}butyl)-1-H-1,2,3-triazole,1-(3-{3-[(2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-1,3-oxazol-4-yl)methoxy]phenyl}propyl)-1H-1,2,3-triazole,or3-(1-{4-[4-({2-[(E)-2-(2,4-difluorophenyl)ethenyl]-1,3-oxazol-4-yl}methoxy)phenyl]butyl}-1H-imidazol-2-yl)-1,2-propanediol,or a salt thereof.
 7. A method for producing a compound as claimed inclaim 1 or a salt thereof comprising reacting a compound represented bythe formula:

wherein X is a leaving group; the other symbols have the same meaningsas defined in claim 1, or a salt thereof, with a compound represented bythe formula:

wherein the symbols have the same meanings as defined in claim 1, or asalt thereof.
 8. A pro-drug of a compound as claimed in claim 1 or asalt thereof.
 9. A pharmaceutical composition containing a compound asclaimed in claim 1 or a salt thereof or a pro-drug thereof.
 10. Apharmaceutical composition as claimed in claim 9, which is a tyrosinekinase inhibitor.
 11. A pharmaceutical composition as claimed in claim9, which is an agent for preventing or treating cancer.
 12. Apharmaceutical composition as claimed in claim 11, wherein the cancer isbreast cancer or prostate cancer.
 13. A pharmaceutical composition asclaimed in claim 11, wherein the cancer is lung cancer.
 14. Apharmaceutical composition which combines a compound as claimed in claim1 or a salt thereof or a pro-drug thereof and other anti-cancer agents.15. A pharmaceutical composition which combines a compound as claimed inclaim 1 or a salt thereof or a pro-drug thereof and hormonal therapeuticagents.
 16. The pharmaceutical composition as claimed in claim 15,wherein the hormonal therapeutic agent is a LH—RH modulator.
 17. Thepharmaceutical composition as claimed in claim 16, wherein the LH—RHmodulator is LH—RH antagonist.
 18. The pharmaceutical composition asclaimed in claim 17, wherein the LH—RH antagonist is leuprorelin or asalt thereof.
 19. A method for inhibiting tyrosine-kinase whichcomprises administering an effective amount of a compound as claimed inclaim 1 or a salt thereof or a pro-drug thereof to mammals.
 20. A methodfor preventing or treating cancer which comprises administering aneffective amount of a compound as claimed in claim 1 or a salt thereofor a pro-drug thereof to mammals.
 21. A method for preventing ortreating cancer which comprises combining (1) administering an effectiveA amount of a compound as claimed in claim 1 or a salt thereof or apro-drug thereof to mammals and (2) 1 to 3 selected from the groupconsisting (i) administering an effective amount of other anti-canceragents to mammals, (ii) administering an effective amount of hormonaltherapeutic agents to mammals and (iii) non-drug therapy.
 22. The methodas claimed in claim 21 wherein non-drug therapy is surgery, hypertensivechemotherapy, genetherapy, thermotherapy, cryotherapy, lasercauterization and/or radiotherapy.
 23. A method for preventing ortreating cancer which comprises administering in combination of aneffective amount of a compound as claimed in claim 1 or a salt thereofor a pro-drug thereof and an effective amount of other anti-canceragents to mammals.
 24. A method for preventing or treating cancer whichcomprises administering in combination of an effective amount of acompound as claimed in claim 1 or a salt thereof or a pro-drug thereofand an effective amount of hormonal therapeutic agents to mammals. 25.The method as claimed in claim 24, wherein the hormonal therapeuticagent is a LH—RH modulator.
 26. The method as claimed in claim 25,wherein the LH—RH modulator is LH—RH antagonist.
 27. The method asclaimed in claim 26, wherein the LH—RH antagonist is leuprorelin or asalt thereof.
 28. A method for preventing or treating cancer whichcomprises administering an effective amount of a compound as claimed inclaim 1 or a salt thereof or a pro-drug thereof to mammals beforesurgery, hypertensive chemotherapy, genetherapy, thermotherapy,cryotherapy, laser cauterization and/or radiotherapy.
 29. A method forpreventing or treating cancer which comprises administering an effectiveamount of a compound as claimed in claim 1 or a salt thereof or apro-drug thereof to mammals after surgery, hypertensive chemotherapy,genetherapy, thermotherapy, cryotherapy, laser cauterization and/orradiotherapy.
 30. A method for preventing or treating cancer whichcomprises administering in combination of an effective amount of acompound as claimed in claim 1 or a salt thereof or a pro-drug thereofand an effective amount of other anti-cancer agents to mammals beforesurgery, hypertensive chemotherapy, genetherapy, thermotherapy,cryotherapy, laser cauterization and/or radiotherapy.
 31. A method forpreventing or treating cancer which comprises administering incombination of an effective amount of a compound as claimed in claim 1or a salt thereof or a pro-drug thereof and an effective amount of otheranti-cancer agents to mammals before surgery, hypertensive chemotherapy,genetherapy, thermotherapy, cryotherapy, laser cauterization and/orradiotherapy.
 32. The method as claimed in claim 31, wherein thehormonal therapeutic agent is a LH—RH modulator.
 33. The method asclaimed in claim 32, wherein the LH—RH modulator is LH—RH antagonist.34. The method as claimed in claim 33, wherein the LH—RH antagonist isleuprorelin or a salt thereof.
 35. A method for preventing or treatingcancer which comprises administering in combination of an effectiveamount of a compound as claimed in claim 1 or a salt thereof or apro-drug thereof and an effective amount of other anti-cancer agents tomammals after surgery, hypertensive chemotherapy, genetherapy,thermotherapy, cryotherapy, laser cauterization and/or radiotherapy. 36.A method for preventing or treating cancer which comprises administeringin combination of an effective amount of a compound as claimed in claim1 or a salt thereof or a pro-drug thereof and an effective amount ofother anti-cancer agents to mammals after surgery, hypertensivechemotherapy, genetherapy, thermotherapy, cryotherapy, lasercauterization and/or radiotherapy.
 37. The method-as claimed in claim36, wherein the hormonal therapeutic agent is a LH—RH modulator.
 38. Themethod as claimed in claim 37, wherein the LH—RH modulator is LH—RHantagonist.
 39. The method as claimed in claim 38, wherein the LH—RHantagonist is leuprorelin or a salt thereof.
 40. Use of a compound asclaimed in claim 1 or a salt thereof or a pro-drug thereof for preparinga tyrosine kinase inhibitor.
 41. Use of a compound as claimed in claim 1or a salt thereof or a pro-drug thereof for preparing an agent forpreventing or treating cancer.
 42. A compound represented by theformula:

wherein R^(1a) is fluoro or trifluoromethyl, X¹ is a leaving group, andn is 3 or 4, or a salt thereof.
 43. A compound as claimed in claim 42,wherein X¹ is a halogen atom.
 44. Use of a compound as claimed in claim42 or a salt thereof for preparing a compound as claimed in claim 1.